1
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Wang X, Zhou J, Xu B. Engaging an engineered PARP-2 catalytic domain mutant to solve the complex structures harboring approved drugs for structure analyses. Bioorg Chem 2025; 160:108471. [PMID: 40228437 DOI: 10.1016/j.bioorg.2025.108471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 04/02/2025] [Accepted: 04/11/2025] [Indexed: 04/16/2025]
Abstract
The PARP-1/2 inhibitors have been approved for the treatment of cancers by modulating the enzymatic activity and/or the trapping ability for damaged DNA of PARP-1 and/or PARP-2, and the selective PARP-1 inhibitors are now attracting considerable attention with an aim to search for drug candidates with an improved safety. Exploring the structural basis of the selectivity and trapping capability of known PARP-1/2 inhibitors would be beneficial for the discovery of the improved inhibitors. Herein, a mutated PARP-2 catalytic domain, designated as catPARP-2SE, was engineered. It could be expressed in an elevated level and had capability to crystalize at 25 °C, which greatly facilitated obtaining PARP-2 crystals. Consequently, the complex structures of Fluzoparib, Pamiparib, Rucaparib, and Niraparib within PARP-2 were achieved. Taking advantage of these complexed structures, the detailed and quantitative analyses of protein-ligand and intra-protein interactions (αB-αF, αJ-αB, αJ-αF, ASL-αD and ASL-αF interfaces) were conducted with quantum chemistry methods (GFN2-xTB and IGMH). It suggested that the residues adjacent to Asp766 in the HD and ASL domains and the αJ-αF and ASL-αD interfaces were closely related to the selectivity and trapping mechanism. These results would provide some insights for the design and development of novel PARP-1/2 inhibitors with improved pharmacodynamic properties.
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Affiliation(s)
- Xiaoyu Wang
- Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Jie Zhou
- Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Bailing Xu
- Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
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2
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Zhao J, Tang B, Shen P, Zeng H, Wei Q. Empowering PARP inhibition through rational combination: Mechanisms of PARP inhibitors and combinations with a focus on the treatment of metastatic castration-resistant prostate cancer. Crit Rev Oncol Hematol 2025; 210:104698. [PMID: 40089046 DOI: 10.1016/j.critrevonc.2025.104698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 02/14/2025] [Accepted: 03/06/2025] [Indexed: 03/17/2025] Open
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors have revolutionized the treatment of many cancers. Metastatic castration-resistant prostate cancer (mCRPC) is an area where PARP inhibitors are intensively studied; the efficacy with PARP inhibitor monotherapy in patients with homologous recombination repair mutations following novel hormonal therapy have prompted the investigation of combination therapy, with adding an androgen receptor pathway inhibitor (ARPI) being one focus of research. Data on PARP inhibitor monotherapy and combination therapy for mCRPC are accumulating, and it is important to navigate through the complex data to inform treatment decision. Here we review the mechanisms of action of PARP inhibitors, their pharmacological properties, the synergistic activity of PARP inhibitors plus other drug classes, and the clinical evidence on monotherapy and combination therapy in patients with mCRPC. We propose key considerations in the selection of agents and treatment sequence for mCRPC, such as efficacy, toxicity profiles, biomarkers, and interactions with concomitant medications.
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Affiliation(s)
- Jinge Zhao
- Department of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Bo Tang
- Department of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Pengfei Shen
- Department of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Hao Zeng
- Department of Urology, West China Hospital, Sichuan University, Chengdu, China.
| | - Qiang Wei
- Department of Urology, West China Hospital, Sichuan University, Chengdu, China.
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3
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Gnanavelou R, Jayaraman M, Jeyaraman J, Girija KR. Computational design and structural insights into quinazoline-based lead molecules for targeting PARP10 in cancer therapy. J Mol Graph Model 2025; 137:109005. [PMID: 40101436 DOI: 10.1016/j.jmgm.2025.109005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 02/28/2025] [Accepted: 03/01/2025] [Indexed: 03/20/2025]
Abstract
Quinazoline scaffolds, a class of nitrogen-containing heterocyclic compounds, are considered a "privileged structure" in drug development due to their broad physiological activities and significant therapeutic potential. Many anti-breast cancer therapies are designed using this pharmacophore. Structural modifications such as halogen substitution and aromatic amino group insertion have been explored to improve the anticancer efficacy of quinazoline derivatives. Breast cancer continues to be the primary cause of cancer-related mortality among women, approximately 670,000 deaths globally in 2022, emphasizing the need for novel therapies. To combat multidrug resistance in breast cancer, new drug candidates targeting the Poly (ADP-ribose) polymerase (PARP) enzyme are being developed to improve chemotherapeutic efficacy and reduce toxicity. In this study, computational screening of 365 quinazoline derivatives was conducted to identify potential PARP inhibitors. Docking based screening identified three quinazoline scaffolds (RFAP77, RISA30, and RISAC) as top hits, demonstrating docking scores ranging from -8.41 to -9.31 kcal/mol and MM-GBSA binding free energy scores between -52.08 and -55.99 kcal/mol, compared to the reference approved inhibitor. ADMET analysis revealed favorable predicted drug-likeness profiles for the identified scaffolds. The structural stability of the docked PARP-ligand complexes was further investigated using molecular dynamics simulations (MDS). The computational simulations revealed significant conformational changes upon ligand binding, as evidenced by RMSD, RMSF, and hydrogen bond analyses. Essential dynamics analysis, including PCA-based FEL mapping, demonstrated energy minima profiles for all top docked PARP complexes. These computational findings highlight the potential of these scaffolds as promising candidates for further development as PARP inhibitors.
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Affiliation(s)
- Revathi Gnanavelou
- Department of Pharmaceutical Chemistry, College of Pharmacy, Mother Theresa Post Graduate and Research Institute of Health Sciences, (A Govt. of Puducherry Institution), Puducherry, 605 006, India
| | - Manikandan Jayaraman
- Structural Biology and Biocomputing Lab, Department of Bioinformatics, Alagappa University, Karaikudi, 630 004, Tamil Nadu, India
| | - Jeyakanthan Jeyaraman
- Structural Biology and Biocomputing Lab, Department of Bioinformatics, Alagappa University, Karaikudi, 630 004, Tamil Nadu, India
| | - Konda Reddy Girija
- Department of Pharmaceutical Chemistry, College of Pharmacy, Mother Theresa Post Graduate and Research Institute of Health Sciences, (A Govt. of Puducherry Institution), Puducherry, 605 006, India.
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4
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Salsi V, Losi F, Salani M, Kaufman PD, Tupler R. Posttranscriptional RNA stabilization of telomeric RNAs FRG2, DBE-T, D4Z4 at human 4q35 in response to genotoxic stress and D4Z4 macrosatellite repeat length. Clin Epigenetics 2025; 17:73. [PMID: 40320530 PMCID: PMC12049803 DOI: 10.1186/s13148-025-01881-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 04/10/2025] [Indexed: 05/08/2025] Open
Abstract
BACKGROUND Reduced copy number of the D4Z4 macrosatellite at human chromosome 4q35 is associated with facioscapulohumeral muscular dystrophy (FSHD). A pervasive idea is that chromatin alterations at the 4q35 locus following D4Z4 repeat unit deletion lead to disease via inappropriate expression of nearby genes. Here, we sought to analyze transcription and chromatin characteristics at specific regions of 4q35 and how these are affected by D4Z4 deletions and exogenous stresses. RESULTS We found that the 4q subtelomere is subdivided into discrete domains, each with characteristic chromatin features associated with distinct gene expression profiles. Centromeric genes within 4q35 (SLC25A4, FAT1 and FRG1) display active histone marks at their promoters. In contrast, poised or repressed markings are present at telomeric loci including FRG2, DBE-T and D4Z4. We discovered that these discrete domains undergo region-specific chromatin changes upon treatment with chromatin enzyme inhibitors or genotoxic drugs. We demonstrated that the 4q35 telomeric FRG2, DBE-T and D4Z4-derived transcripts are induced upon DNA damage to levels inversely correlated with the D4Z4 repeat number, are stabilized through posttranscriptional mechanisms upon DNA damage and are bound to chromatin. CONCLUSION Our study reveals unforeseen biochemical features of RNAs from clustered transcription units within the 4q35 subtelomere. Specifically, the FRG2, DBE-T and D4Z4-derived transcripts are chromatin-associated and are stabilized posttranscriptionally after induction by genotoxic stress. Remarkably, the extent of this response is modulated by the copy number of the D4Z4 repeats, raising new hypotheses about their regulation and function in human biology and disease.
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Affiliation(s)
- Valentina Salsi
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via G. Campi 287, 41125, Modena, Italy
| | - Francesca Losi
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via G. Campi 287, 41125, Modena, Italy
| | - Monica Salani
- Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, MA, 02114, USA
| | - Paul D Kaufman
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Rossella Tupler
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via G. Campi 287, 41125, Modena, Italy.
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5
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Han Y, Wei L. Novel clinical potential of poly (ADP‑ribose) polymerase inhibitors in triple‑negative breast cancer: Mechanistic insights and clinical applications (Review). Oncol Lett 2025; 29:215. [PMID: 40093872 PMCID: PMC11907691 DOI: 10.3892/ol.2025.14961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 02/12/2025] [Indexed: 03/19/2025] Open
Abstract
Breast cancer is one of the most prevalent malignant tumors worldwide, and triple-negative breast cancer (TNBC) presents a major therapeutic challenge due to the lack of effective targeted treatment options. Poly (ADP-ribose) polymerase (PARP) plays a critical role in DNA damage repair, and its inhibitors have shown significant therapeutic efficacy in patients with TNBC exhibiting breast cancer susceptibility gene (BRCA) mutations. The present review aimed to analyze the molecular mechanisms of cell death induced by DNA damage related to PAR and PARP, thoroughly exploring the role of PARP in regulatory pathways. Additionally, it intended to highlight clinical trials and therapeutic outcomes of PARP inhibitors currently used in TNBC treatment. In particular, the current review delves into the mechanisms of drug resistance, such as BRCA mutation reversion and PARP protein trapping, and examines potential strategies to overcome PARP inhibitor resistance in the future. Ultimately, the present study aims to offer novel perspectives and research directions for further optimizing the application of PARP inhibitors in TNBC therapy.
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Affiliation(s)
- Yu Han
- School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430000, P.R. China
| | - Lei Wei
- School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430000, P.R. China
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6
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Gabellier L, Bosetta E, Heiblig M, Sarry JE. Metabolism and therapeutic response in acute myeloid leukemia with IDH1/2 mutations. Trends Cancer 2025; 11:475-490. [PMID: 39955197 DOI: 10.1016/j.trecan.2025.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/16/2025] [Accepted: 01/24/2025] [Indexed: 02/17/2025]
Abstract
Pathogenic variants of isocitrate dehydrogenase 1 and 2 (IDH1/2) genes are present in approximately 20% of acute myeloid leukemia (AML) cases, resulting in the oncometabolite R-2-hydroxyglutarate (R-2-HG). The accumulation of R-2-HG in leukemic cells and in their niche induces epigenetic modifications, profound rewiring of the cellular metabolism, and microenvironmental remodeling. These changes promote cellular differentiation bias, enhancing the survival and proliferation of leukemic cells, and thus playing a pivotal role in leukemogenesis and resistance to standard AML therapy. This review focuses on the different perspectives offered by studying metabolism and resistance to standard treatments in AML with IDH1 or IDH2 pathogenic variants, for the development of new biomarkers and therapeutic solutions.
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MESH Headings
- Humans
- Isocitrate Dehydrogenase/genetics
- Isocitrate Dehydrogenase/metabolism
- Isocitrate Dehydrogenase/antagonists & inhibitors
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Mutation
- Glutarates/metabolism
- Drug Resistance, Neoplasm/genetics
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
- Epigenesis, Genetic
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
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Affiliation(s)
- Ludovic Gabellier
- Service d'Hématologie Clinique, Centre Hospitalier Universitaire de Montpellier, Montpellier, France; Team «Ubiquitin family in hematological malignancies», Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, Université de Montpellier, Montpellier, France
| | - Enzo Bosetta
- Centre de Recherches en Cancérologie de Toulouse, U1037, Inserm, Université de Toulouse, Toulouse, France
| | - Maël Heiblig
- Service d'Hématologie Clinique, Hôpital Lyon Sud Pierre-Bénite, Lyon, France; Team «Lymphoma Immuno-Biology», Inserm U1111, CNRS UMR5308, Université Claude Bernard, Lyon I - ENS de Lyon, Faculté de Médecine Lyon-Sud, Lyon, France
| | - Jean-Emmanuel Sarry
- Centre de Recherches en Cancérologie de Toulouse, U1037, Inserm, Université de Toulouse, Toulouse, France.
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7
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Verrou E, Koutoukoglou P, Kontana E, Gogolopoulos S, Sevastoudi A, Daiou A, Dalampira D, Triantafyllou T, Radounislis A, Karampatzakis N, Papadopoulou T, Giannouli E, Bouliopoulos GP, Yiannaki E, Tzimou M, Polychronidou G, Papalexandri A, Boutis A, Katodritou E. Incidence, characteristics and outcome of therapy-related myeloid neoplasms in women with epithelial ovarian cancer after exposure to poly-ADPribose polymerase inhibitors: A cancer center experience. Int J Cancer 2025; 156:1686-1691. [PMID: 39686855 DOI: 10.1002/ijc.35299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 11/29/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024]
Abstract
Poly(ADP-ribose) polymerase inhibitors (PARPi) target the DNA repair pathways and have been established in epithelial ovarian cancer (EOC) as maintenance therapy inducing prolonged survival. However, recently published data showed that PARPi may increase the risk of therapy-related myeloid neoplasms (t-MN) including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Herein, we investigated the incidence, characteristics, and management of t-MN among EOC patients after exposure to PARPi in a Greek Cancer Center. We analyzed 112 consecutive EOC patients treated with PARPi with a median age of 58 years (range 28-84). Olaparib and Niraparib were used in 90 and 22 patients, respectively. The median number of previous chemotherapy lines and duration of treatment with PARPi were 2 (range 1-9) lines and 12 (range 2-24) months, respectively. The incidence of t-MN among patients treated with PARPi was 3.57% (4/112). Patients with t-MN were distributed as follows: t-MDS: 1, t-MDS/AML: 1, t-AML: 2. We observed adverse cytogenetic features in t-MN patients leading to dismal prognosis. In conclusion, in accordance with previous real-world reports, we confirm a notable risk for t-MN in EOC patients treated with PARPi. As PARPi are an emerging therapy for many neoplasms, there is an unmet clinical need to identify patients who are considered at high risk for developing t-MN post-therapy with PARPi in order to introduce potential preventive strategies.
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Affiliation(s)
- Evgenia Verrou
- Hematology Department, Theagenio Cancer Hospital, Thessaloniki, Greece
| | | | - Evangelia Kontana
- Third Department of Clinical Oncology, Theagenio Cancer Hospital, Thessaloniki, Greece
| | - Stavros Gogolopoulos
- Second Department of Clinical Oncology, Theagenio Cancer Hospital, Thessaloniki, Greece
| | | | - Aikaterini Daiou
- Hematology Department, Theagenio Cancer Hospital, Thessaloniki, Greece
| | - Dimitra Dalampira
- Hematology Department, Theagenio Cancer Hospital, Thessaloniki, Greece
| | | | | | | | | | - Eleni Giannouli
- Immunology Laboratory, Theagenio Cancer Hospital, Thessaloniki, Greece
| | | | - Efthalia Yiannaki
- Hematology Laboratory, Theagenio Cancer Hospital, Thessaloniki, Greece
| | - Maria Tzimou
- Second Department of Clinical Oncology, Theagenio Cancer Hospital, Thessaloniki, Greece
| | | | - Apostolia Papalexandri
- Molecular Diagnostics Laboratory, Hematology Department and BMT Unit, George Papanikolaou General Hospital, Thessaloniki, Greece
| | - Anastasios Boutis
- Third Department of Clinical Oncology, Theagenio Cancer Hospital, Thessaloniki, Greece
| | - Eirini Katodritou
- Hematology Department, Theagenio Cancer Hospital, Thessaloniki, Greece
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8
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Hayes MN, Cohen-Gogo S, Kee L, Xiong X, Weiss A, Layeghifard M, Ladumor Y, Valencia-Sama I, Rajaselvam A, Kaplan DR, Villani A, Shlien A, Morgenstern DA, Irwin MS. DNA damage response deficiency enhances neuroblastoma progression and sensitivity to combination PARP and ATR inhibition. Cell Rep 2025; 44:115537. [PMID: 40220294 DOI: 10.1016/j.celrep.2025.115537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 02/03/2025] [Accepted: 03/17/2025] [Indexed: 04/14/2025] Open
Abstract
Sequencing of neuroblastoma (NB) tumors has revealed genetic alterations in genes involved in DNA damage response (DDR) pathways. However, roles for specific alterations of DDR genes in pediatric solid tumors remain poorly understood. To address this, mutations in the DDR pathway including Brca2, Atm, and Palb2 were incorporated into an established zebrafish MYCN transgenic model (Tg(dbh:EGFP-MYCN)). These mutations enhance NB formation and metastasis and result in upregulation of cell-cycle checkpoint and DNA damage repair signatures, revealing molecular vulnerabilities in DDR-deficient NB. DDR gene knockdown in zebrafish and human NB cells increases sensitivity to the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, and this effect is enhanced by inhibition of the ataxia telangiectasia and rad3-related (ATR) kinase. This work provides in vivo evidence demonstrating that alterations in certain DDR-pathway genes promote aggressive NB and supports combination PARP + ATR inhibitor therapy for NB patients with tumors harboring specific genetic alterations in DDR.
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Affiliation(s)
- Madeline N Hayes
- Developmental, Stem Cell and Cancer Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
| | - Sarah Cohen-Gogo
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Lynn Kee
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Xueting Xiong
- Developmental, Stem Cell and Cancer Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Alex Weiss
- Developmental, Stem Cell and Cancer Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Mehdi Layeghifard
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Yagnesh Ladumor
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | | | - Anisha Rajaselvam
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - David R Kaplan
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Neurosciences and Mental Health Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Anita Villani
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Adam Shlien
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Daniel A Morgenstern
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Meredith S Irwin
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
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9
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Ortega P, Bournique E, Li J, Sanchez A, Santiago G, Harris BR, Striepen J, Maciejowski J, Green AM, Buisson R. Mechanism of DNA replication fork breakage and PARP1 hyperactivation during replication catastrophe. SCIENCE ADVANCES 2025; 11:eadu0437. [PMID: 40238882 DOI: 10.1126/sciadv.adu0437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 03/11/2025] [Indexed: 04/18/2025]
Abstract
Ataxia telangiectasia and Rad3-related (ATR) inhibition triggers a surge in origin firing, resulting in increased levels of single-stranded DNA (ssDNA) that rapidly deplete all available RPA. This leaves ssDNA unprotected and susceptible to breakage, a phenomenon known as replication catastrophe. However, the mechanism by which unprotected ssDNA breaks remains unclear. Here, we reveal that APOBEC3B is the key enzyme targeting unprotected ssDNA at replication forks, initiating a reaction cascade that induces fork collapse and poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Mechanistically, we demonstrate that uracils generated by APOBEC3B at replication forks are removed by UNG2, resulting in abasic sites that are subsequently cleaved by APE1 endonuclease. Moreover, we show that APE1-mediated DNA cleavage is the critical enzymatic step for PARP1 hyperactivation in cells, regardless of how abasic sites are generated on DNA. Last, we demonstrate that APOBEC3B-induced PARP1 trapping and DNA double-strand breaks drive cell sensitivity to ATR inhibition, creating a context of synthetic lethality when coupled with PARP inhibitors.
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Affiliation(s)
- Pedro Ortega
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
| | - Elodie Bournique
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
| | - Junyi Li
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
| | - Ambrocio Sanchez
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
| | - Gisselle Santiago
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
| | - Brooke R Harris
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
- Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Josefine Striepen
- Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - John Maciejowski
- Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Abby M Green
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
- Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Rémi Buisson
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA
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10
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Gu Kang B, Kang SU, Jin Kim J, Kwon JS, Gagné JP, Yun Lee S, Kim S, Lee KS, Ha S, Seop Jeong J, Lee YI, Zhu H, Kim D, Poirier GG, Chul Kang H, Dawson VL, Dawson TM. Proteome-wide microarray-based screening of PAR-binding proteins. Nucleic Acids Res 2025; 53:gkaf300. [PMID: 40239998 PMCID: PMC12000866 DOI: 10.1093/nar/gkaf300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 02/18/2025] [Accepted: 03/31/2025] [Indexed: 04/18/2025] Open
Abstract
Poly (ADP-ribose) (PAR) plays a crucial role in intracellular signaling and scaffolding through covalent modification or non-covalent binding to target proteins. The non-covalent PAR binding proteome (PARylome) has not been extensively characterized. Here we performed a PAR-binding screen using a human protein microarray that covers most of the human proteome to characterize the non-covalent binding PARylome. A total of 356 PAR-binding proteins were identified. The PAR-binding PARylome suggests that PAR binding regulates a variety of biological processes beyond DNA damage signaling and DNA repair. Proteins that may be reprogrammed by PAR binding include signaling molecules, transcription factors, nucleic acid binding proteins, calcium binding proteins, ligases, oxidoreductases, enzymes, transferases, hydrolases, and receptors. The global database of PAR-binding proteins that we established will be a valuable tool for further in-depth analysis of the role of PARylation in a wide range of biological contexts.
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Affiliation(s)
- Bong Gu Kang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Sung-Ung Kang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Jae Jin Kim
- Genomic Instability Research Center, Ajou University, School of Medicine, Suwon 16499, Korea
- Department of Physiology, Ajou University School of Medicine, Suwon 16499, Korea
| | - Ji-Sun Kwon
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Jean-Philippe Gagné
- Oncology Division, CHU de Québec Research Center - CHUL, Quebec City, QCG1V 4G2, Canada
| | - Seo Yun Lee
- Genomic Instability Research Center, Ajou University, School of Medicine, Suwon 16499, Korea
- Department of Physiology, Ajou University School of Medicine, Suwon 16499, Korea
| | - Soyeon Kim
- Genomic Instability Research Center, Ajou University, School of Medicine, Suwon 16499, Korea
- Department of Physiology, Ajou University School of Medicine, Suwon 16499, Korea
| | - Karl S Lee
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Shinwon Ha
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Jun Seop Jeong
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- High Through Put Biology Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Yun-Il Lee
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Heng Zhu
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- High Through Put Biology Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Dongsan Kim
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Guy G Poirier
- Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Québec, QC G1V 0A6, Canada
| | - Ho Chul Kang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Genomic Instability Research Center, Ajou University, School of Medicine, Suwon 16499, Korea
- Department of Physiology, Ajou University School of Medicine, Suwon 16499, Korea
| | - Valina L Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Ted M Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
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11
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Sengar D, Pathan NS, Gajbhiye V. D-bait: A siDNA for regulation of DNA-protein kinases against DNA damage and its implications in cancer. Int J Pharm 2025; 673:125416. [PMID: 40024452 DOI: 10.1016/j.ijpharm.2025.125416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/31/2025] [Accepted: 02/26/2025] [Indexed: 03/04/2025]
Abstract
siDNA fragments, also called Dbait and Pbait, are small DNA oligonucleotides of 30-32 base pairs that cause impairment in DNA repair pathways. Like siRNA and miRNA molecules, which lead to the degradation of mRNA molecules through the Argonaute and Drosha machinery, respectively, Dbait molecules act as false DNA damage signals and trigger and exhaust the DNA repair machinery. In normal cells with no significant DNA damage, the influence of these molecules is negligible. However, in cancer, when there is heavy DNA damage due to replication and anticancer therapies, the cancer cell is heavily dependent on DNA repair proteins to keep the genome intact and limit breaks. This phenomenon primarily occurs during radiation therapy, as significant DNA damage surpasses several DNA repair mechanisms, causing an accumulation of unrepaired lesions and ultimately leading to cell death. This review explores the therapeutic capacity of siDNA molecules in cancer treatment by stimulating the repair mechanisms in cells that depend on DNA repair pathways. For aggressive malignancies such as glioblastoma, prostate cancer, and colorectal cancer, the use of siDNA as a radiosensitizer, especially when combined with other treatments, increases the vulnerability of tumor cells to radiation-induced DNA damage, hence potentially enhancing therapy results.
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Affiliation(s)
- Devyani Sengar
- Nanobioscience Group, Agharkar Research Institute, Pune 411004, India; Savitribai Phule Pune University, Pune 411007, India
| | - Nida Sayed Pathan
- Nanobioscience Group, Agharkar Research Institute, Pune 411004, India; Savitribai Phule Pune University, Pune 411007, India
| | - Virendra Gajbhiye
- Nanobioscience Group, Agharkar Research Institute, Pune 411004, India; Savitribai Phule Pune University, Pune 411007, India.
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12
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Liang H, Li S, Peng X, Xiao H. Overview of the epigenetic/cytotoxic dual-target inhibitors for cancer therapy. Eur J Med Chem 2025; 285:117235. [PMID: 39788061 DOI: 10.1016/j.ejmech.2024.117235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/24/2024] [Accepted: 12/31/2024] [Indexed: 01/12/2025]
Abstract
Epigenetic dysregulation plays a pivotal role in the initiation and progression of various cancers, influencing critical processes such as tumor growth, invasion, migration, survival, apoptosis, and angiogenesis. Consequently, targeting epigenetic pathways has emerged as a promising strategy for anticancer drug discovery in recent years. However, the clinical efficacy of epigenetic inhibitors, such as HDAC inhibitors, has been limited, often accompanied by resistance. To overcome these challenges, innovative therapeutic approaches are required, including the combination of epigenetic inhibitors with cytotoxic agents or the design of dual-acting inhibitors that target both epigenetic and cytotoxic pathways. In this review, we provide a comprehensive overview of the structures, biological functions and inhibitors of epigenetic regulators (such as HDAC, LSD1, PARP, and BET) and cytotoxic targets (including tubulin and topoisomerase). Furthermore, we discuss recent advancement of combination therapies and dual-target inhibitors that target both epigenetic and cytotoxic pathways, with a particular focus on recent advances, including rational drug design, pharmacodynamics, pharmacokinetics, and clinical applications.
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Affiliation(s)
- Hailiu Liang
- School of Medical and Information Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 341000, PR China
| | - Shuqing Li
- School of Medical and Information Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 341000, PR China
| | - Xiaopeng Peng
- School of Medical and Information Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 341000, PR China; Jiangxi Provincial Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou, 341000, PR China.
| | - Hao Xiao
- School of Medical and Information Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 341000, PR China; Jiangxi Provincial Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou, 341000, PR China.
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13
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Li Y, Miao W, Yuan C, Tang J, Zhong N, Jin Y, Hu Y, Tang Y, Wang S. PARP inhibitor boost the efficacy of photothermal therapy to TNBC through enhanced DNA damage and inhibited homologous recombination repair. Drug Deliv Transl Res 2025; 15:955-967. [PMID: 38954244 DOI: 10.1007/s13346-024-01650-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2024] [Indexed: 07/04/2024]
Abstract
Triple-negative breast cancer (TNBC) could benefit from PARP inhibitors (PARPi) for their frequent defective homologous recombination repair (HR). However, the efficacy of PARPi is limited by their lower bioavailability and high susceptibility to drug resistance, so it often needs to be combined with other treatments. Herein, polydopamine nanoparticles (PDMN) were constructed to load Olaparib (AZD) as two-channel therapeutic nanoplatforms. The PDMN has a homogeneous spherical structure around 100 nm and exhibits a good photothermal conversion efficiency of 62.4%. The obtained AZD-loaded nanoplatform (PDMN-AZD) showed enhanced antitumor effects through the combination of photothermal therapy (PTT) and PARPi. By western blot and flow cytometry, we found that PTT and PARPi could exert synergistic antitumor effects by further increasing DNA double-strand damage (DSBs) and enhancing HR defects. The strongest therapeutic effect of PDMN-AZD was observed in a BRCA-deficient mouse tumor model. In conclusion, the PDMN-AZD nanoplatform designed in this study demonstrated the effectiveness of PTT and PARPi for synergistic treatment of TNBC and preliminarily explained the mechanism.
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Affiliation(s)
- Yang Li
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhoulu, Nanjing, Jiangsu, China
| | - Wenfang Miao
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhoulu, Nanjing, Jiangsu, China
| | - Chen Yuan
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhoulu, Nanjing, Jiangsu, China
| | - Jiajia Tang
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhoulu, Nanjing, Jiangsu, China
| | - Nan Zhong
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhoulu, Nanjing, Jiangsu, China
| | - Yingying Jin
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhoulu, Nanjing, Jiangsu, China
| | - Yongzhi Hu
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhoulu, Nanjing, Jiangsu, China
| | - Yuxia Tang
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhoulu, Nanjing, Jiangsu, China
| | - Shouju Wang
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhoulu, Nanjing, Jiangsu, China.
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14
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Tzang CC, Wu HW, Luo CA, Li YT, Kang YF, Hsieh CM, Lee CY, Hsu TC, Tzang BS. Efficacy and safety of PARP inhibitors in prostate cancer: An umbrella review of systematic reviews and meta-analyses. Crit Rev Oncol Hematol 2025; 207:104609. [PMID: 39761938 DOI: 10.1016/j.critrevonc.2024.104609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/24/2024] [Accepted: 12/27/2024] [Indexed: 01/12/2025] Open
Abstract
Prostate cancer is a significant cause of cancer-related deaths in men. Poly (ADP-ribose) polymerase inhibitors (PARPi) have been shown to improve progression-free survival, especially in patients with BRCA1/2 mutations and deficiencies in homologous recombination repair (HRR). We conducted systematic reviews and meta-analyses and found that PARPi, combined with androgen receptor inhibitors, significantly improved overall survival (OS) and progression-free survival (PFS) in BRCA1/2-mutant and HRR-deficient patients. PARPi therapies increased the incidence of adverse events (AEs), including fatigue, nausea, anemia, neutropenia, and thrombocytopenia. Among different PARP inhibitors, Olaparib, Talazoparib, and Rucaparib demonstrated the strongest efficacy in improving OS and PFS but were also linked to higher rates of AEs. Combination therapies with PARPi and hormonal treatments proved more effective than monotherapy, especially in genetically targeted subgroups like BRCA1/2-mutant patients. This umbrella review demonstrates that PARPi treatment significantly improves clinical outcomes, particularly in BRCA1/2-mutant and HRR-deficient mCRPC patients.
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Affiliation(s)
- Chih-Chen Tzang
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Hui-Wen Wu
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Chiao-An Luo
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Yong-Tang Li
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Yuan-Fu Kang
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Chia-Ming Hsieh
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Chen-Yu Lee
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Tsai-Ching Hsu
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 402, Taiwan; Immunology Research Center, Chung Shan Medical University, Taichung 402, Taiwan.
| | - Bor-Show Tzang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 402, Taiwan; Immunology Research Center, Chung Shan Medical University, Taichung 402, Taiwan; Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.
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15
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Najafi N, Fatemi MH. Computational design of PARP-1 inhibitors: QSAR, molecular docking, virtual screening, ADMET, and molecular dynamics simulations for targeted drug development. SAR AND QSAR IN ENVIRONMENTAL RESEARCH 2025; 36:205-246. [PMID: 40289719 DOI: 10.1080/1062936x.2025.2480859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Accepted: 03/10/2025] [Indexed: 04/30/2025]
Abstract
Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors have shown promise in treating various cancers with homologous recombination repair deficiencies, particularly in breast and ovarian cancers harbouring BRCA1/2 mutations. This study aimed to identify and optimize novel PARP-1 inhibitors using the phthalazinone scaffold, known for forming strong and selective interactions with the active site of PARP-1. Through a combination of Quantitative Structure-Activity Relationship (QSAR) modelling, molecular docking simulations, and virtual screening, we discovered compounds with significant anticancer potential. Both the Multiple Linear Regression (MLR) and Support Vector Machines (SVM) models, utilizing four selected molecular descriptors, demonstrated high predictive efficiency for inhibitory activity (MLR: r2 = 0.944, Q2cv (cross-validated correlation coefficient) = 0.921, root mean square error (RMSE) = 0.249; SVM: r2 = 0.947, Q2cv = 0.887, RMSE = 0.245). Molecular docking studies revealed that several new compounds exhibited strong interactions with key amino acids GLY 227A, MET 229A, PHE 230A, and TYR 246A within the PARP-1 active site, similar to those observed in reference inhibitors Olaparib and AZD2461. Then, the top-ranked compound's (3a) ligand-protein complex underwent a 200 ns molecular dynamics (MD) simulation, confirming stable binding and revealing a robust set of intermolecular interactions maintained under physiological conditions.
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Affiliation(s)
- N Najafi
- Laboratory of Chemometrics, Faculty of Chemistry, University of Mazandaran, Babolsar, Iran
| | - M H Fatemi
- Laboratory of Chemometrics, Faculty of Chemistry, University of Mazandaran, Babolsar, Iran
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16
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Shanmugam N, Chatterjee S, Cisneros GA. Impact of a Cancer-Associated Mutation on Poly(ADP-ribose) Polymerase1 Inhibition. J Phys Chem B 2025; 129:2175-2186. [PMID: 39962867 PMCID: PMC12005076 DOI: 10.1021/acs.jpcb.4c07960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/26/2025]
Abstract
Poly(ADP-ribose) polymerase1 (PARP1) plays a vital role in DNA repair, and its inhibition in cancer cells may cause cell apoptosis. In this study, we investigated the effects of a PARP1 variant, V762A, which is strongly associated with several cancers in humans, on the inhibition of PARP1 by three FDA-approved inhibitors: niraparib, rucaparib, and talazoparib. Specifically, we compared the inhibition of the mutant to that of wild-type (WT) PARP1. Additionally, we investigated how the mutation influences the binding of these inhibitors to PARP1. Our work suggests that while mutant PARP1 exhibits only minor differences in residual fluctuations, backbone deviations, and residue motion correlations compared to the WT under niraparib and rucaparib inhibitions, it shows significant and distinct differences in these features when inhibited by talazoparib. Among the three inhibitions, talazoparib inhibition uniquely lowers the average residue fluctuations in the mutant than the WT including lower fluctuations of mutant's N- and C-terminal residues in the catalytic domain, conserved H-Y-E traid residues, and donor loop (D-loop) residues which are important for catalysis more effectively than other inhibitions. However, talazoparib also significantly enhances destabilizing interactions between the mutation site in the HD domain in the mutant than WT. Further, among the three inhibitions, talazoparib inhibition uniquely and significantly disrupts the functional fluctuations of terminal regions in the mutant, which are otherwise present in the WT. The mutation and inhibition do not significantly affect PARP1's essential dynamics. Lastly, these inhibitors bind to the V762A mutant more effectively than to the WT, with similar binding free energies between them.
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Affiliation(s)
- Neel Shanmugam
- Department of Chemistry, University of North Texas, Denton, Texas 76201, United States; Present Address: Department of Computer Science, Columbia University, New York, New York 10027, United States
| | - Shubham Chatterjee
- Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, Texas 75080, United States
| | - G. Andrés Cisneros
- Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, Texas 75080, United States; Department of Physics, University of Texas at Dallas, Richardson, Texas 75080, United States
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17
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Varga D, Szentirmai A, Szarka A. Research for a Common Thread: Insights into the Mechanisms of Six Potential Anticancer Agents. Molecules 2025; 30:1031. [PMID: 40076255 PMCID: PMC11901853 DOI: 10.3390/molecules30051031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/24/2025] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
Our research group aimed for the optimization of pharmacologic ascorbate (Ph-Asc)-induced cancer cell death. To reduce the required time and resources needed for development, an in silico system biological approach, an already approved medication, and a mild bioactive compound were used in our previous studies. It was revealed that both Ph-Asc and resveratrol (RES) caused DSBs in the DNA, and chloroquine (CQ) treatment amplified the cytotoxic effect of both Ph-Asc and RES in an autophagy independent way. In the present study, we aimed at the further clarification of the cytotoxic mechanism of Ph-Asc, CQ, and RES by comparing their DNA damaging abilities, effects on the cells' bioenergetic status, ROS, and lipid ROS generation abilities with those of the three currently investigated compounds (menadione, RSL3, H2O2). It could be assessed that the induction of DSBs is certainly a common point of their mechanism of action; furthermore, the observed cancer cell death due to the investigated treatments are independent of the bioenergetic status. Contrary to other investigated compounds, the DNA damaging effect of CQ seemed to be ROS independent. Surprisingly, the well-known ferroptosis inducer RSL3 was unable to induce lipid peroxidation in the pancreas ductal adenocarcinoma (PDAC) Mia PaCa-2 cell line. At the same time, it induced DSBs in the DNA, and the RSL3-induced cell death could not be suspended by the well-known ferroptosis inhibitors. All these observations suggest the ferroptosis resistance of this cell line. The observed DNA damaging effect of RSL3 definitely creates a new perspective in anticancer research.
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Affiliation(s)
- Dóra Varga
- Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary; (D.V.); (A.S.)
- Biotechnology Model Laboratory, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary
| | - Anna Szentirmai
- Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary; (D.V.); (A.S.)
- Biotechnology Model Laboratory, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary
| | - András Szarka
- Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary; (D.V.); (A.S.)
- Biotechnology Model Laboratory, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary
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18
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Hussain M, Khadka P, Pekhale K, Kulikowicz T, Gray S, May A, Croteau DL, Bohr VA. RECQL4 requires PARP1 for recruitment to DNA damage, and PARG dePARylation facilitates its associated role in end joining. Exp Mol Med 2025; 57:264-280. [PMID: 39870799 PMCID: PMC11799438 DOI: 10.1038/s12276-024-01383-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 10/03/2024] [Accepted: 10/16/2024] [Indexed: 01/29/2025] Open
Abstract
RecQ helicases, highly conserved proteins with pivotal roles in DNA replication, DNA repair and homologous recombination, are crucial for maintaining genomic integrity. Mutations in RECQL4 have been associated with various human diseases, including Rothmund-Thomson syndrome. RECQL4 is involved in regulating major DNA repair pathways, such as homologous recombination and nonhomologous end joining (NHEJ). RECQL4 has more prominent single-strand DNA annealing activity than helicase activity. Its ability to promote DNA damage repair and the precise role of its DNA annealing activity in DNA repair are unclear. Here we demonstrate that PARP1 interacts with RECQL4, increasing its single-stranded DNA strand annealing activity. PARP1 specifically promoted RECQL4 PARylation at both its N- and C-terminal regions, promoting RECQL4 recruitment to DNA double-strand breaks (DSBs). Inhibition or depletion of PARP1 significantly diminished RECQL4 recruitment and occupancy at specific DSB sites on chromosomes. After DNA damage, PARG dePARylated RECQL4 and stimulated its end-joining activity. RECQL4 actively displaced replication protein A from single-stranded DNA, promoting microhomology annealing in vitro. Furthermore, depletion of PARP1 or RECQL4 substantially impacted classical-NHEJ- and alternative-NHEJ-mediated DSB repair. Consequently, the combined activities of PARP1, PARG and RECQL4 modulate DNA repair.
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Affiliation(s)
- Mansoor Hussain
- Section on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Prabhat Khadka
- Section on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Komal Pekhale
- Section on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Tomasz Kulikowicz
- Section on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Samuel Gray
- Section on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Alfred May
- Section on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Deborah L Croteau
- Section on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
- Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Vilhelm A Bohr
- Section on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
- Dept of ICMM, University of Copenhagen, Copenhagn, Denmark.
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19
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Jain A, Barge A, Parris CN. Combination strategies with PARP inhibitors in BRCA-mutated triple-negative breast cancer: overcoming resistance mechanisms. Oncogene 2025; 44:193-207. [PMID: 39572842 PMCID: PMC11746151 DOI: 10.1038/s41388-024-03227-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 11/04/2024] [Accepted: 11/07/2024] [Indexed: 01/22/2025]
Abstract
Triple-negative breast cancer (TNBC) is a particularly aggressive breast cancer subtype, characterised by a higher incidence in younger women, rapid metastasis, and a generally poor prognosis. Patients with TNBC and BRCA mutations face additional therapeutic challenges due to the cancer's intrinsic resistance to conventional therapies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have emerged as a promising targeted treatment for BRCA-mutated TNBC, exploiting vulnerabilities in the homologous recombination repair (HRR) pathway. However, despite initial success, the efficacy of PARPis is often compromised by the development of resistance mechanisms, including HRR restoration, stabilisation of replication forks, reduced PARP1 trapping, and drug efflux. This review explores latest breakthroughs in overcoming PARPi resistance through combination therapies. These strategies include the integration of PARPis with chemotherapy, immunotherapy, antibody-drug conjugates, and PI3K/AKT pathway inhibitors. These combinations aim to enhance the therapeutic efficacy of PARPis by targeting multiple cancer progression pathways. The review also discusses the evolving role of PARPis within the broader treatment paradigm for BRCA-mutated TNBC, emphasising the need for ongoing research and clinical trials to optimise combination strategies. By tackling the challenges associated with PARPi resistance and exploring novel combination therapies, this review sheds light on the future possibilities for improving outcomes for patients with BRCA-mutated TNBC.
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Affiliation(s)
- Aditi Jain
- Edinburgh Medical School: Biomedical Sciences, The University of Edinburgh, Edinburgh, UK.
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20
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Bottillo I, Sciarra A, Bevilacqua G, Gentilucci A, Sciarra B, Santarelli V, Salciccia S, Bacigalupo F, Pastacaldi F, Ciccone MP, De Marchis L, Santini D, Magliocca FM, Merenda E, Forte F, Grammatico P. Early Detection of the Pathogenetic Variants of Homologous Recombination Repair Genes in Prostate Cancer: Critical Analysis and Experimental Design. BIOLOGY 2025; 14:117. [PMID: 40001885 PMCID: PMC11851859 DOI: 10.3390/biology14020117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 01/13/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025]
Abstract
It has been shown that the pathogenic variants (PVs) of the DNA Damage Response (DDR) genes, whether of a germinal or somatic nature, represent a predictive biomarker of high sensitivity to treatment with inhibitors of the enzyme poly-ADP-ribose polymerase (PARP) in patients with hormone-resistant metastatic prostate cancer (HRPCa). Moreover, the detection of PVs of the Homologous Recombination Repair (HRR) genes in PCa patients can help to define the patient's prognosis and the choice of the therapeutic procedure. Among men with metastatic PCa, the frequency of PVs in HRR genes ranges from 11% to 33%, which is a significantly higher rate compared to non-metastatic PCa, where the incidence is between 5% and 10%. Next-Generation Sequencing (NGS) results were more commonly obtained from newly acquired somatic samples compared to archived samples (prostate biopsy or prostatectomy). We developed an experimental multidisciplinary prospective study in patients with a new diagnosis of high-risk PCa at biopsy. The aim was to evaluate the presence of PVs of different HRR genes in patients with the first diagnosis of PCa in relation to a metastatic or non-metastatic stage, tumor aggressiveness, and early risk of progression. Among 43 initial tumor samples from 22 patients, 25 samples from 12 patients were selected for library preparation based on their DNA concentration and quality. After the NGS, 14 different DNA variants were prioritized. Oncogenetic and likely oncogenetic variants were found in the ATM, BRCA1, PTEN, KMT2D, and CDH1 genes. Moreover, variants of uncertain significance were found in ATM, DDR2, FANCA, FOXA1, PLCB4, PTCH1, and RB1.
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Affiliation(s)
- Irene Bottillo
- Division of Medical Genetics, Department of Experimental Medicine, San Camillo-Forlanini Hospital, Sapienza University, 00161 Rome, Italy; (I.B.); (F.B.); (F.P.); (M.P.C.); (P.G.)
| | - Alessandro Sciarra
- Department “Materno Infantile e Scienze Urologiche”, University Sapienza, Viale Policlinico 155, 00161 Rome, Italy; (G.B.); (A.G.); (V.S.); (S.S.)
| | - Giulio Bevilacqua
- Department “Materno Infantile e Scienze Urologiche”, University Sapienza, Viale Policlinico 155, 00161 Rome, Italy; (G.B.); (A.G.); (V.S.); (S.S.)
| | - Alessandro Gentilucci
- Department “Materno Infantile e Scienze Urologiche”, University Sapienza, Viale Policlinico 155, 00161 Rome, Italy; (G.B.); (A.G.); (V.S.); (S.S.)
| | - Beatrice Sciarra
- Department of Pharmaceutic Chemistry, University Sapienza, 00161 Rome, Italy;
| | - Valerio Santarelli
- Department “Materno Infantile e Scienze Urologiche”, University Sapienza, Viale Policlinico 155, 00161 Rome, Italy; (G.B.); (A.G.); (V.S.); (S.S.)
| | - Stefano Salciccia
- Department “Materno Infantile e Scienze Urologiche”, University Sapienza, Viale Policlinico 155, 00161 Rome, Italy; (G.B.); (A.G.); (V.S.); (S.S.)
| | - Francesca Bacigalupo
- Division of Medical Genetics, Department of Experimental Medicine, San Camillo-Forlanini Hospital, Sapienza University, 00161 Rome, Italy; (I.B.); (F.B.); (F.P.); (M.P.C.); (P.G.)
| | - Francesco Pastacaldi
- Division of Medical Genetics, Department of Experimental Medicine, San Camillo-Forlanini Hospital, Sapienza University, 00161 Rome, Italy; (I.B.); (F.B.); (F.P.); (M.P.C.); (P.G.)
| | - Maria Pia Ciccone
- Division of Medical Genetics, Department of Experimental Medicine, San Camillo-Forlanini Hospital, Sapienza University, 00161 Rome, Italy; (I.B.); (F.B.); (F.P.); (M.P.C.); (P.G.)
| | - Laura De Marchis
- Department Oncology, University Sapienza, 00161 Rome, Italy; (L.D.M.); (D.S.)
| | - Daniele Santini
- Department Oncology, University Sapienza, 00161 Rome, Italy; (L.D.M.); (D.S.)
| | | | - Elisabetta Merenda
- Department of Pathology, University Sapienza, 00161 Rome, Italy; (F.M.M.); (E.M.)
| | - Flavio Forte
- Urology Unit, Vannini Hospital, 00190 Rome, Italy;
| | - Paola Grammatico
- Division of Medical Genetics, Department of Experimental Medicine, San Camillo-Forlanini Hospital, Sapienza University, 00161 Rome, Italy; (I.B.); (F.B.); (F.P.); (M.P.C.); (P.G.)
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Wu M, Jiang Y, Zhang D, Wu Y, Jin Y, Liu T, Mao X, Yu H, Xu T, Chen Y, Huang W, Che J, Zhang B, Liu T, Lin N, Dong X. Discovery of a potent PARP1 PROTAC as a chemosensitizer for the treatment of colorectal cancer. Eur J Med Chem 2025; 282:117062. [PMID: 39602992 DOI: 10.1016/j.ejmech.2024.117062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 11/29/2024]
Abstract
Given the vulnerability of colorectal cancer (CRC) patients could not obtain a sustained benefit from chemotherapy, combination therapy is frequently employed as a treatment strategy. Targeting PARP1 blockade exhibit specific toxicity towards tumor cells with BRCA1 or BRCA2 mutations through synthetic lethality. This study focuses on developing a series of potent PROTACs targeting PARP1 in order to enhance the sensitivity of CRC cells with BRCA1 or BRCA2 mutations to chemotherapy. Compound C6, obtained based on precise structural optimization of the linker, has been shown to effectively degrade PARP1 with a DC50 value of 58.14 nM. Furthermore, C6 significantly increased the cytotoxic efficacy of SN-38, an active metabolite of Irinotecan, in BRCA-mutated CRC cells, achieving a favorable combination index (CI) of 0.487. In conclusion, this research underscores the potential benefits of employing a combination therapy that utilizes PAPRP1 degrader C6 alongside Irinotecan for CRC patients harboring BRCA mutations in CRC.
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Affiliation(s)
- Mingfei Wu
- Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yiming Jiang
- Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Daoming Zhang
- Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yiquan Wu
- Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yuyuan Jin
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310058, China
| | - Tao Liu
- Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Xinfei Mao
- Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Hengyuan Yu
- Institute of Modern Chinese Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Tengfei Xu
- Institute of Modern Chinese Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yong Chen
- Institute of Modern Chinese Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Wenhai Huang
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310058, China
| | - Jinxin Che
- Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310009, China
| | - Bo Zhang
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310024, China; Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou, 310024, China
| | - Tao Liu
- Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310009, China.
| | - Nengming Lin
- Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310024, China; Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou, 310024, China.
| | - Xiaowu Dong
- Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310009, China.
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22
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Dhanavath N, Bisht P, Jamadade MS, Murti K, Wal P, Kumar N. Olaparib: A Chemosensitizer for the Treatment of Glioblastoma. Mini Rev Med Chem 2025; 25:374-385. [PMID: 39444180 DOI: 10.2174/0113895575318854241014101928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 08/29/2024] [Accepted: 09/07/2024] [Indexed: 10/25/2024]
Abstract
Glioblastoma (GBM) is the most prevalent and deadly primary brain tumor. The current treatment for GBM includes adjuvant chemotherapy with temozolomide (TMZ), radiation therapy, and surgical tumor excision. There is still an issue because 50% of patients with GBM who get TMZ have low survival rates due to TMZ resistance. The activation of several DNA repair mechanisms, such as Base Excision Repair (BER), DNA Mismatch Repair (MMR), and O-6- Methylguanine-DNA Methyltransferase (MGMT), is the main mechanism via which TMZ resistance develops. The zinc-finger DNA-binding enzyme poly (ADP-ribose) polymerase-1 (PARP1), which is activated by binding to DNA breaks, affects the activation of the MGMT, BER, and MMR pathway deficiency, which results in TMZ resistance in GBM. PARP inhibitors have been studied recently as sensitizing medications to increase TMZ potency. The first member of the PARP inhibitor family to be identified was Olaparib. It inhibits PARP1 and PARP2, which causes apoptosis in cancer cells and DNA strand break. Olaparib is currently investigated as a radio- and/or chemo-sensitizer in addition to being used as a single agent because it may increase the cytotoxic effects of other treatments. This review addresses Olaparib and its significance in treating TMZ resistance in GBM.
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Affiliation(s)
- Naresh Dhanavath
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Export Promotion Industrial Park (EPIP), Zandaha Road, NH322, Hajipur, Bihar, 844102, India
| | - Priya Bisht
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Export Promotion Industrial Park (EPIP), Zandaha Road, NH322, Hajipur, Bihar, 844102, India
| | - Mohini Santosh Jamadade
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Export Promotion Industrial Park (EPIP), Zandaha Road, NH322, Hajipur, Bihar, 844102, India
| | - Krishna Murti
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER), Export Promotion Industrial Park (EPIP), Zandaha Road, NH322, Hajipur, Bihar, 844102, India
| | - Pranay Wal
- Institute of Pharmacy, Pranveer Singh Institute of Technology, Kanpur, Uttar Pradesh, India
| | - Nitesh Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Export Promotion Industrial Park (EPIP), Zandaha Road, NH322, Hajipur, Bihar, 844102, India
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23
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Kam CMT, Tauber AL, Zunk MS, McDermott CM, Levonis SM, Schweiker SS. Novel inhibitors of PARP1 and PARP14: design, synthesis, and potentiation of cisplatin efficacy in cancer. Future Med Chem 2025; 17:35-58. [PMID: 39691063 DOI: 10.1080/17568919.2024.2437972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 11/25/2024] [Indexed: 12/19/2024] Open
Abstract
BACKGROUND Poly(ADP-ribose) polymerase (PARP) is a superfamily of enzymes involved in cell survival. Both PARP1 and PARP14 are overexpressed in malignancies. No clinically approved PARP14 inhibitors are available, and PARP1 inhibitors are generally nonspecific, resulting in a need for a more diverse library of selective PARP1 and PARP14 inhibitors. MATERIALS AND METHODS Based on the previous lead compounds 1 and 2, 26 novel compounds were designed, synthesized, and screened against PARP1 and PARP14. Compounds with the best in vitro inhibitory results were further screened against PARP2, PARP3, PARP5a, PARP7, and PARP15. RESULTS AND CONCLUSION The 26 novel compounds demonstrated a lesser inhibitory effect than the lead compounds. Compounds 1 and 2 were further investigated using in vitro cell viability assays, which revealed that cells treated with either lead PARP inhibitor and cisplatin in combination had significantly lower survival rates than those treated with cisplatin alone. At 10 µM, the combination showed more significant cell survival reduction, suggesting greater inhibition of PARP increases lethality, particularly in HeLa and PC-3 cell lines at 96 h and beyond.
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Affiliation(s)
- Caleb M T Kam
- Medicinal Chemistry Group, Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia
| | - Amanda L Tauber
- Medicinal Chemistry Group, Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia
| | - Matthew S Zunk
- School of Pharmacy and Medical Sciences, Griffith University, Southport, Queensland, Australia
| | - Catherine M McDermott
- Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia
| | - Stephan M Levonis
- Medicinal Chemistry Group, Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia
| | - Stephanie S Schweiker
- Medicinal Chemistry Group, Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia
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24
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Tong J, Chen B, Volpi T, Li Y, Ellison PA, Cai Z. Current Advances in PARP1-Targeted Theranostics. J Labelled Comp Radiopharm 2025; 68:e4135. [PMID: 39995212 DOI: 10.1002/jlcr.4135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Revised: 02/07/2025] [Accepted: 02/13/2025] [Indexed: 02/26/2025]
Abstract
Poly (ADP-ribose) polymerase 1 (PARP1) plays critical roles in DNA repair, chromatin regulation, and cellular equilibrium, positioning it as a pivotal target for therapeutic interventions in cancer and central nervous system (CNS) disorders. PARP1 responds to oxidative stress and DNA damage through PARylation, influencing energy depletion, survival, inflammation, and genomic regulation in many biological scenarios. PARP inhibitors (PARPis) have demonstrated efficacy against cancers harboring defective homologous recombination repair pathways, notably those linked to BRCA mutations. PARP1-targeted PET imaging enables patient stratification, treatment assessment, and PARPi pharmacodynamic evaluation in cancers and other pathophysiological conditions. Importantly, PARP1-targeted theranostics have emerged for both diagnostic imaging and therapeutic applications in multiple types of cancers, representing a pivotal advancement in personalized oncology. However, its application in brain tumors is limited by the heterogeneous integrity of the blood brain barrier (BBB) and the blood-tumor barrier. Thus, the development of BBB-penetrant PARP1 tracers remains an unmet need for imaging brain cancers. This review summarizes the current landscape of radiopharmaceuticals and radioligands targeting PARP1, detailing their pharmacological characteristics and potential clinical uses. Furthermore, this review discusses PARP1 tracers that can cross the BBB, underscoring their potential applications in neurooncology and other neurological disorders.
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Affiliation(s)
- Jie Tong
- Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut, USA
| | - Baosheng Chen
- Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut, USA
| | - Tommaso Volpi
- Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut, USA
| | - Yawen Li
- Department of Radiation Oncology, University of Washington, Seattle, Washington, USA
| | - Paul A Ellison
- Department of Medical Physics, University of Wisconsin, Madison, Wisconsin, USA
| | - Zhengxin Cai
- Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut, USA
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25
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Matthews B, Wong-Brown M, Liu D, Yee C, Dickson KA, Schneider J, Islam S, Head R, Martin JH, Ford CE, Marsh DJ, Bowden NA. Drug repurposing screen targeting PARP identifies cytotoxic activity of efavirenz in high-grade serous ovarian cancer. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200911. [PMID: 39802157 PMCID: PMC11719850 DOI: 10.1016/j.omton.2024.200911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/14/2024] [Accepted: 11/21/2024] [Indexed: 01/16/2025]
Abstract
Drug repurposing has potential to improve outcomes for high-grade serous ovarian cancer (HGSOC). Repurposing drugs with PARP family binding activity may produce cytotoxic effects through the multiple mechanisms of PARP including DNA repair, cell-cycle regulation, and apoptosis. The aim of this study was to determine existing drugs that have PARP family binding activity and can be repurposed for treatment of HGSOC. In silico ligand-based virtual screening (BLAZE) was used to identify drugs with potential PARP-binding activity. The list was refined by dosing, known cytotoxicity, lipophilicity, teratogenicity, and side effects. The highest ranked drug, efavirenz, progressed to in vitro testing. Molecularly characterized HGSOC cell lines, 3D hydrogel-encapsulated models, and patient-derived organoid models were used to determine the IC50 for efavirenz, cell death, apoptosis, PARP1 enzyme expression, and activity in intact cancer cells following efavirenz treatment. The IC50 for efavirenz was 26.43-45.85 μM for cells in two dimensions; 27.81 μM-54.98 μM in three dimensions, and 14.52 μM-42.27 μM in HGSOC patient-derived organoids. Efavirenz decreased cell viability via inhibition of PARP; increased CHK2 and phosphor-RB; increased cell-cycle arrest via decreased CDK2; increased γH2AX, DNA damage, and apoptosis. The results of this study suggest that efavirenz may be a viable treatment for HGSOC.
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Affiliation(s)
- Bayley Matthews
- Drug Repurposing and Medicines Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW 2289, Australia
| | - Michelle Wong-Brown
- Drug Repurposing and Medicines Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW 2289, Australia
| | - Dongli Liu
- Gynaecological Cancer Research Group, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - Christine Yee
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Kristie-Ann Dickson
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Jennifer Schneider
- Drug Repurposing and Medicines Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW 2289, Australia
| | - Saiful Islam
- Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Richard Head
- Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Jennifer H. Martin
- Drug Repurposing and Medicines Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW 2289, Australia
| | - Caroline E. Ford
- Gynaecological Cancer Research Group, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - Deborah J. Marsh
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Nikola A. Bowden
- Drug Repurposing and Medicines Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW 2289, Australia
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Kang C, Kim J, Jeong Y, Yoo JW, Jung Y. Colon-Targeted Poly(ADP-ribose) Polymerase Inhibitors Synergize Therapeutic Effects of Mesalazine Against Rat Colitis Induced by 2,4-Dinitrobenzenesulfonic Acid. Pharmaceutics 2024; 16:1546. [PMID: 39771525 PMCID: PMC11728683 DOI: 10.3390/pharmaceutics16121546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/14/2024] [Accepted: 11/25/2024] [Indexed: 01/16/2025] Open
Abstract
Background/Objectives: In addition to oncological applications, poly(ADP-ribose) polymerase (PARP) inhibitors have potential as anti-inflammatory agents. Colon-targeted delivery of PARP inhibitors has been evaluated as a pharmaceutical strategy to enhance their safety and therapeutic efficacy against gut inflammation. Methods: Colon-targeted PARP inhibitors 5-aminoisoquinoline (5-AIQ) and 3-aminobenzamide (3-AB) were designed and synthesized by azo coupling with salicylic acid (SA), yielding 5-AIQ azo-linked with SA (AQSA) and 3-AB azo-linked with SA (ABSA). Additional conjugation of AQSA with acidic amino acids yielded glutamic acid-conjugated AQSA (AQSA-Glu) and aspartic acid-conjugated AQSA, which further increased the hydrophilicity of AQSA. Results: The distribution coefficients of PARP inhibitors were lowered by chemical modifications, which correlated well with drug permeability via the Caco-2 cell monolayer. All derivatives were effectively converted to their corresponding PARP inhibitors in the cecal contents. Compared with observations in the oral administration of PARP inhibitors, AQSA-Glu and ABSA resulted in the accumulation of much greater amounts of each PARP inhibitor in the cecum. ABSA accumulated mesalazine (5-ASA) in the cecum to a similar extent as sulfasalazine (SSZ), a colon-targeted 5-ASA prodrug. In the DNBS-induced rat colitis model, AQSA-Glu enhanced the anticolitic potency of 5-AIQ. Furthermore, ABSA was more effective against rat colitis than SSZ or AQSA-Glu, and the anticolitic effects of AQSA-Glu were augmented by combined treatment with a colon-targeted 5-ASA prodrug. In addition, the colon-targeted delivery of PARP inhibitors substantially reduced their systemic absorption. Conclusions: Colon-targeted PARP inhibitors may improve the therapeutic and toxicological properties of inhibitors and synergize the anticolitic effects of 5-ASA.
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Affiliation(s)
| | | | | | | | - Yunjin Jung
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea; (C.K.); (J.K.); (Y.J.); (J.-W.Y.)
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27
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Chernyshova I, Vasil'eva I, Moor N, Ivanisenko N, Kutuzov M, Abramova T, Zakharenko A, Lavrik O. Aminomethylmorpholino Nucleosides as Novel Inhibitors of PARP1 and PARP2: Experimental and Molecular Modeling Analyses of Their Selectivity and Mechanism of Action. Int J Mol Sci 2024; 25:12526. [PMID: 39684238 DOI: 10.3390/ijms252312526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/08/2024] [Accepted: 11/10/2024] [Indexed: 12/18/2024] Open
Abstract
Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2) play a key role in DNA repair. As major sensors of DNA damage, they are activated to produce poly(ADP-ribose). PARP1/PARP2 inhibitors have emerged as effective drugs for the treatment of cancers with BRCA deficiencies. Here, we explored aminomethylmorpholino and aminomethylmorpholino glycine nucleosides as inhibitors of PARP1 and PARP2, using different enzymatic assays. The compounds bearing thymine or 5-Br(I)-uracil bases displayed the highest inhibition potency, with all of them being more selective toward PARP1. Interaction of the inhibitors with the NAD+ binding cavity of PARP1 (PARP2) suggested by the mixed-type inhibition was demonstrated by molecular docking and the RoseTTAFold All-Atom AI-model. The best PARP1 inhibitors characterized by the inhibition constants in the range of 12-15 µM potentiate the cytotoxicity of hydrogen peroxide by displaying strong synergism. The inhibitors revealed no impact on PARP1/PARP2 affinity for DNA, while they reduced the dissociation rate of the enzyme-DNA complex upon the autopoly(ADP-ribosyl)ation reaction, thus providing evidence that their mechanism of action for PARP trapping is due primarily to catalytic inhibition. The most active compounds were shown to retain selectivity toward PARP1, despite the reduced inhibition potency in the presence of histone PARylation factor 1 (HPF1) capable of regulating PARP1/PARP2 catalytic activity and ADP-ribosylation reaction specificity. The inhibitors obtained seem to be promising for further research as potential drugs.
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Affiliation(s)
- Irina Chernyshova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Inna Vasil'eva
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Nina Moor
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Nikita Ivanisenko
- Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
- AIRI, 123112 Moscow, Russia
| | - Mikhail Kutuzov
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Tatyana Abramova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Alexandra Zakharenko
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Olga Lavrik
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
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28
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Shanmugam N, Chatterjee S, Cisneros GA. Impact of a Cancer-Associated Mutation on Poly(ADP-ribose) Polymerase1 Inhibition. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.13.623412. [PMID: 39605557 PMCID: PMC11601374 DOI: 10.1101/2024.11.13.623412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Poly(ADP-ribose) polymerase1 (PARP1) plays a vital role in DNA repair and its inhibition in cancer cells may cause cell apoptosis. In this study, we investigated the effects of a PARP1 variant, V762A, which is strongly associated with several cancers in humans, on the inhibition of PARP1 by three FDA approved inhibitors: niraparib, rucaparib and talazoparib. Our work suggests that these inhibitors bind to the V762A mutant more effectively than to the wild-type (WT), with similar binding free energies between them. Talazoparib inhibition uniquely lowers the average residue fluctuations in the mutant than the WT including lower fluctuations of mutant's N- and C-terminal residues, conserved H-Y-E traid residues and donor loop (D-loop) residues which important for catalysis more effectively than other inhibitions. However, talazoparib also enhances destabilizing interactions between the mutation site in the HD domain in the mutant than WT. Further, talazoparib inhibition significantly disrupts the functional fluctuations of terminal regions in the mutant, which are otherwise present in the WT. Lastly, the mutation and inhibition do not significantly affect PARP1's essential dynamics.
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Affiliation(s)
- Neel Shanmugam
- Department of Chemistry, University of North Texas, Denton, TX 76201, USA
| | - Shubham Chatterjee
- Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, 75080, USA
| | - G. Andrés Cisneros
- Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, 75080, USA
- Department of Physics, University of Texas at Dallas, Richardson, TX, 75080, USA
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Ortega P, Bournique E, Li J, Sanchez A, Santiago G, Harris BR, Green AM, Buisson R. ATR safeguards replication forks against APOBEC3B-induced toxic PARP1 trapping. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.14.623607. [PMID: 39605722 PMCID: PMC11601322 DOI: 10.1101/2024.11.14.623607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
ATR is the master safeguard of genomic integrity during DNA replication. Acute inhibition of ATR with ATR inhibitor (ATRi) triggers a surge in origin firing, leading to increased levels of single-stranded DNA (ssDNA) that rapidly deplete all available RPA. This leaves ssDNA unprotected and susceptible to breakage, a phenomenon known as replication catastrophe. However, the mechanism by which unprotected ssDNA breaks remains unclear. Here, we reveal that APOBEC3B is the key enzyme targeting unprotected ssDNA at replication forks, triggering a reaction cascade that induces fork collapse and PARP1 hyperactivation. Mechanistically, we demonstrate that uracils generated by APOBEC3B at replication forks are removed by UNG2, creating abasic sites that are subsequently cleaved by APE1 endonuclease. Moreover, we demonstrate that APE1-mediated DNA cleavage is the critical enzymatic step for PARP1 trapping and hyperactivation in cells, regardless of how abasic sites are generated on DNA. Finally, we show that APOBEC3B-induced toxic PARP1 trapping in response to ATRi drives cell sensitivity to ATR inhibition, creating to a context of synthetic lethality when combined with PARP inhibitors. Together, these findings reveal the mechanisms that cause replication forks to break during replication catastrophe and explain why ATRi-treated cells are particularly sensitive to PARP inhibitors.
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Affiliation(s)
- Pedro Ortega
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
| | - Elodie Bournique
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
| | - Junyi Li
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
| | - Ambrocio Sanchez
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
| | - Gisselle Santiago
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
| | - Brooke R. Harris
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
- Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Abby M. Green
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
- Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Rémi Buisson
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
- Center for Virus Research, University of California Irvine, Irvine, CA, USA
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA
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30
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Al-Rahahleh RQ, Sobol RW. Poly-ADP-ribosylation dynamics, signaling, and analysis. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2024; 65:315-337. [PMID: 39221603 PMCID: PMC11604531 DOI: 10.1002/em.22623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 08/15/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024]
Abstract
ADP-ribosylation is a reversible post-translational modification that plays a role as a signaling mechanism in various cellular processes. This modification is characterized by its structural diversity, highly dynamic nature, and short half-life. Hence, it is tightly regulated at many levels by cellular factors that fine-tune its formation, downstream signaling, and degradation that together impacts cellular outcomes. Poly-ADP-ribosylation is an essential signaling mechanism in the DNA damage response that mediates the recruitment of DNA repair factors to sites of DNA damage via their poly-ADP-ribose (PAR)-binding domains (PBDs). PAR readers, encoding PBDs, convey the PAR signal to mediate cellular outcomes that in some cases can be dictated by PAR structural diversity. Several PBD families have been identified, each with variable PAR-binding affinity and specificity, that also recognize and bind to distinct parts of the PAR chain. PARylation signaling has emerged as an attractive target for the treatment of specific cancer types, as the inhibition of PAR formation or degradation can selectively eliminate cancer cells with specific DNA repair defects and can enhance radiation or chemotherapy response. In this review, we summarize the key players of poly-ADP-ribosylation and its regulation and highlight PBDs as tools for studying PARylation dynamics and the expanding potential to target PARylation signaling in cancer treatment.
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Affiliation(s)
- Rasha Q. Al-Rahahleh
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School & Legorreta Cancer Center, Brown University, Providence, RI 02912
| | - Robert W. Sobol
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School & Legorreta Cancer Center, Brown University, Providence, RI 02912
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Deng K, Li Q, Lu L, Wang L, Cheng Z, Wang S. Proteasome and PARP1 dual-target inhibitor for multiple myeloma: Fluzoparib. Biochem Biophys Rep 2024; 39:101781. [PMID: 39071914 PMCID: PMC11279668 DOI: 10.1016/j.bbrep.2024.101781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 06/05/2024] [Accepted: 07/05/2024] [Indexed: 07/30/2024] Open
Abstract
One of the current mainstream treatments for multiple myeloma (MM) is chemotherapy. However, due to the high clonal heterogeneity and genomic complexity of MM, single-target drugs have limited efficacy and are prone to drug resistance. Therefore, there is an urgent need to develop multi-target drugs against MM. We screened drugs that simultaneously inhibit poly(ADP-ribose) polymerase 1 (PARP1) and 20S proteasome through computer-aided drug discovery (CADD) techniques, and explored the binding mode and dynamic stability of selected inhibitor to proteasome through Molecular biology (MD) simulation method. Thus, the dual-target inhibition effect of fluzoparib was proposed for the first time, and the ability of dual-target inhibition and tumor killing was explored at the enzyme, cell and animal level, respectively. This provides a theoretical and experimental basis for exploring multi-target inhibitory drugs for cancers.
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Affiliation(s)
- Kai Deng
- Department of Orthopedics, Shenzhen Longhua District Central Hospital, Shenzhen, Guangdong, China
| | - Qiongqiong Li
- Department of Hematology, Shenzhen Longhua District Central Hospital, Shenzhen, Guangdong, China
| | - Lina Lu
- Department of Hematology, Shenzhen Longhua District Central Hospital, Shenzhen, Guangdong, China
| | - Luting Wang
- Department of Hematology, Shenzhen Longhua District Central Hospital, Shenzhen, Guangdong, China
| | - Zhiyong Cheng
- Department of Hematology, Baoding No.1 Hospital, Baoding, Hebei, China
| | - Suyun Wang
- Department of Hematology, Shenzhen Longhua District Central Hospital, Shenzhen, Guangdong, China
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32
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Kumar Kore R, Shirbhate E, Singh V, Mishra A, Veerasamy R, Rajak H. New Investigational Drug's Targeting Various Molecular Pathways for Treatment of Cervical Cancer: Current Status and Future Prospects. Cancer Invest 2024; 42:627-642. [PMID: 38966000 DOI: 10.1080/07357907.2024.2373841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 06/24/2024] [Indexed: 07/06/2024]
Abstract
Currently, cervical cancer (CC) is the fourth recorded widespread cancer among women globally. There are still many cases of metastatic or recurring disease discovered, despite the incidence and fatality rates declining due to screening identification and innovative treatment approaches. Palliative chemotherapy continues to be the standard of care for patients who are not contenders for curative therapies like surgery and radiotherapy. This article seeks to provide a thorough and current summary of therapies that have been looked into for the management of CC. The authors emphasize the ongoing trials while reviewing the findings of clinical research. Agents that use biological mechanisms to target different molecular pathways such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), poly ADP-ribosepolymerase (PARP), and epigenetic biological mechanisms epitomize and offer intriguing research prospects.
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Affiliation(s)
- Rakesh Kumar Kore
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, Chhattisgarh, India
| | - Ekta Shirbhate
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, Chhattisgarh, India
| | - Vaibhav Singh
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, Chhattisgarh, India
| | - Achal Mishra
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, Chhattisgarh, India
| | | | - Harish Rajak
- Department of Pharmacy, Guru Ghasidas University, Bilaspur, Chhattisgarh, India
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Knight W, Margaryan T, Sanai N, Tovmasyan A. A validated LC-MS/MS method for determination of neuro-pharmacokinetic behavior of niraparib in brain tumor patients. J Pharm Biomed Anal 2024; 245:116150. [PMID: 38657366 DOI: 10.1016/j.jpba.2024.116150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 04/12/2024] [Accepted: 04/14/2024] [Indexed: 04/26/2024]
Abstract
Niraparib is a potent and orally bioavailable inhibitor of poly (ADP-ribose) polymerase (PARP) with high specificity for isoforms 1 and 2. It has been approved by the U.S. Food and Drug Administration for ovarian cancer maintenance therapy and is currently under development for various cancers, including glioblastoma. To assess central nervous system (CNS) penetration of niraparib in glioblastoma patients, a novel bioanalytical method was developed to measure total and unbound niraparib levels in human brain tumor tissue and cerebrospinal fluid (CSF). The method was validated using plasma as a surrogate matrix over the concentration range of 1-10,000 nM on an LC-MS/MS system. The MS/MS detection was conducted in positive electrospray ionization mode, while chromatography was performed using a Kinetex™ PS C18 column with a total 3.5-minute gradient elution run time. The maximum coefficient of variation for both intra- and inter-day precision was 10.6%, with accuracy ranging from 92.8% - 118.5% across all matrices. Niraparib was stable in human brain homogenate for at least 6 hours at room temperature (RT) and 32 days at -20°C, as well as in stock and working solutions for at least 21 hours (RT) and 278 days (4°C). Equilibrium dialysis experiments revealed the fractions unbound of 0.05 and 0.16 for niraparib in human brain and plasma, respectively. The validated method is currently employed to assess niraparib levels in human glioblastoma tissue, CSF, and plasma in an ongoing trial on newly diagnosed glioblastoma and recurrent IDH1/2(+) ATRX mutant glioma patients (NCT05076513). Initial results of calculated total (Kp) and unbound (Kp,uu) tumor-to-plasma partition coefficients indicate significant brain penetration ability of niraparib in glioblastoma patients.
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Affiliation(s)
- William Knight
- Ivy Brain Tumor Center, Barrow Neurological Institute, Phoenix, AZ 85013, USA
| | - Tigran Margaryan
- Ivy Brain Tumor Center, Barrow Neurological Institute, Phoenix, AZ 85013, USA
| | - Nader Sanai
- Ivy Brain Tumor Center, Barrow Neurological Institute, Phoenix, AZ 85013, USA
| | - Artak Tovmasyan
- Ivy Brain Tumor Center, Barrow Neurological Institute, Phoenix, AZ 85013, USA.
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Sellars E, Savguira M, Wu J, Cancelliere S, Jen M, Krishnan R, Hakem A, Barsyte-Lovejoy D, Hakem R, Narod SA, Kotsopoulos J, Salmena L. A high-throughput approach to identify BRCA1-downregulating compounds to enhance PARP inhibitor sensitivity. iScience 2024; 27:110180. [PMID: 38993666 PMCID: PMC11238136 DOI: 10.1016/j.isci.2024.110180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 04/29/2024] [Accepted: 06/01/2024] [Indexed: 07/13/2024] Open
Abstract
PARP inhibitors (PARPi) are efficacious in BRCA1-null tumors; however, their utility is limited in tumors with functional BRCA1. We hypothesized that pharmacologically reducing BRCA1 protein levels could enhance PARPi effectiveness in BRCA1 wild-type tumors. To identify BRCA1 downregulating agents, we generated reporter cell lines using CRISPR-mediated editing to tag endogenous BRCA1 protein with HiBiT. These reporter lines enable the sensitive measurement of BRCA1 protein levels by luminescence. Validated reporter cells were used in a pilot screen of epigenetic-modifying probes and a larger screen of more than 6,000 compounds. We identified 7 compounds that could downregulate BRCA1-HiBiT expression and synergize with olaparib. Three compounds, N-acetyl-N-acetoxy chlorobenzenesulfonamide (NANAC), A-443654, and CHIR-124, were validated to reduce BRCA1 protein levels and sensitize breast cancer cells to the toxic effects of olaparib. These results suggest that BRCA1-HiBiT reporter cells hold promise in developing agents to improve the clinical utility of PARPi.
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Affiliation(s)
- Erin Sellars
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Women's College Research Institute, Women's College Hospital, Toronto, ON M5S 1B2, Canada
| | - Margarita Savguira
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Jie Wu
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Sabrina Cancelliere
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Mark Jen
- Lunenfeld-Tanenbaum Research Institute, Network Biology Collaborative Centre, High-Throughput Screening, Mt. Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada
| | - Rehna Krishnan
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Anne Hakem
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Dalia Barsyte-Lovejoy
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Razqallah Hakem
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Steven A Narod
- Women's College Research Institute, Women's College Hospital, Toronto, ON M5S 1B2, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada
| | - Joanne Kotsopoulos
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Women's College Research Institute, Women's College Hospital, Toronto, ON M5S 1B2, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada
| | - Leonardo Salmena
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Women's College Research Institute, Women's College Hospital, Toronto, ON M5S 1B2, Canada
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Pan JW, Tan ZC, Ng PS, Zabidi MMA, Nur Fatin P, Teo JY, Hasan SN, Islam T, Teoh LY, Jamaris S, See MH, Yip CH, Rajadurai P, Looi LM, Taib NAM, Rueda OM, Caldas C, Chin SF, Lim J, Teo SH. Gene expression signature for predicting homologous recombination deficiency in triple-negative breast cancer. NPJ Breast Cancer 2024; 10:60. [PMID: 39030225 PMCID: PMC11271517 DOI: 10.1038/s41523-024-00671-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 07/10/2024] [Indexed: 07/21/2024] Open
Abstract
Triple-negative breast cancers (TNBCs) are a subset of breast cancers that have remained difficult to treat. A proportion of TNBCs arising in non-carriers of BRCA pathogenic variants have genomic features that are similar to BRCA carriers and may also benefit from PARP inhibitor treatment. Using genomic data from 129 TNBC samples from the Malaysian Breast Cancer (MyBrCa) cohort, we developed a gene expression-based machine learning classifier for homologous recombination deficiency (HRD) in TNBCs. The classifier identified samples with HRD mutational signature at an AUROC of 0.93 in MyBrCa validation datasets and 0.84 in TCGA TNBCs. Additionally, the classifier strongly segregated HRD-associated genomic features in TNBCs from TCGA, METABRIC, and ICGC. Thus, our gene expression classifier may identify triple-negative breast cancer patients with homologous recombination deficiency, suggesting an alternative method to identify individuals who may benefit from treatment with PARP inhibitors or platinum chemotherapy.
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Affiliation(s)
- Jia-Wern Pan
- Cancer Research Malaysia, Subang Jaya, Malaysia.
| | | | - Pei-Sze Ng
- Cancer Research Malaysia, Subang Jaya, Malaysia
| | | | | | | | | | - Tania Islam
- Department of Surgery, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Li-Ying Teoh
- Department of Surgery, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Suniza Jamaris
- Department of Surgery, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Mee-Hoong See
- Department of Surgery, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | | | - Pathmanathan Rajadurai
- Subang Jaya Medical Centre, Subang Jaya, Malaysia
- Jeffrey Cheah School of Medicine & Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya, Malaysia
| | - Lai-Meng Looi
- Department of Pathology, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Nur Aishah Mohd Taib
- Department of Surgery, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Oscar M Rueda
- Cancer Research UK, Cambridge Institute & Department of Oncology, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - Carlos Caldas
- Cancer Research UK, Cambridge Institute & Department of Oncology, Li Ka Shing Centre, Robinson Way, Cambridge, UK
- NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
| | - Suet-Feung Chin
- Cancer Research UK, Cambridge Institute & Department of Oncology, Li Ka Shing Centre, Robinson Way, Cambridge, UK
| | - Joanna Lim
- Cancer Research Malaysia, Subang Jaya, Malaysia
| | - Soo-Hwang Teo
- Cancer Research Malaysia, Subang Jaya, Malaysia
- University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
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Lin C, Liu C, Hu P, Zou Z, Sun G. Design, synthesis, biological evaluation of novel piperidine-based derivatives as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Bioorg Chem 2024; 148:107455. [PMID: 38772289 DOI: 10.1016/j.bioorg.2024.107455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 04/24/2024] [Accepted: 05/12/2024] [Indexed: 05/23/2024]
Abstract
Poly(ADP-ribose) polymerase-1 (PARP-1) is a crucial member of DNA repair enzymes responsible for repairing DNA single-strand breaks. Developing PARP inhibitors based on synthetic lethality strategies is an effective approach for treating breast cancer and other diseases. In this study, a series of novel piperidine-based benzamide derivatives were designed and synthesized using structure-based drug design principles. The anticancer activities of these compounds were evaluated against five human cancer cell lines (MDA-MB-436, CAPAN-1, SW-620, HepG2, SKOV3, and PC3) and the preliminary structure-activity relationships were delineated. Among the compounds, 6a and 15d demonstrated potent antiproliferative effects against MDA-MB-436 cells with IC50 values of 8.56 ± 1.07 μM and 6.99 ± 2.62 μM, respectively. Furthermore, both compounds exhibited excellent inhibitory activity against PARP-1, with IC50 values of 8.33 nM and 12.02 nM, respectively. Mechanistic investigations revealed that 6a and 15d effectively inhibited colony formation and cell migration of HCT116 cells. Moreover, they induced apoptosis by upregulating the expression of Bax and cleaved Caspase-3, while downregulating the expression of Caspase-3 and Bcl-2 in HCT116 cells. Based on its impressive pharmacodynamic data in vitro, we conducted a study to evaluate the efficacy of 15d in a xenograft tumor model in mice when used in combination with cytotoxic agents. Collectively, these findings suggest that 15d could be promising drug candidates worthy of further investigation.
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Affiliation(s)
- Chao Lin
- Yantai Institute of Materia Medica, Shandong 264000, China
| | - Chang Liu
- School of Pharmacy, Naval Medical University, Shanghai, 200433, China
| | - Panpan Hu
- School of Anesthesiology, Naval Medical University, Shanghai, 200433 , China
| | - Zui Zou
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai , 200433 , China; School of Anesthesiology, Naval Medical University, Shanghai, 200433 , China.
| | - Geng Sun
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai , 200433 , China; School of Anesthesiology, Naval Medical University, Shanghai, 200433 , China.
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37
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Yu L, Wang YD, Yan ZW, Zhang LY, Li S. Development of erythrina-based PARP-1/FTase dual-target inhibitors against lung cancer epithelial-mesenchymal transition (EMT) in vivo and in vitro. Bioorg Chem 2024; 148:107480. [PMID: 38772291 DOI: 10.1016/j.bioorg.2024.107480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 05/07/2024] [Accepted: 05/18/2024] [Indexed: 05/23/2024]
Abstract
A novel series of erythrina derivatives as PARP-1/FTase inhibitors were synthesized, and evaluated for their biological activities. Compound T9 had excellent inhibitory effects on cell viability (A549: IC50 = 1.74 μM; A549/5-Fu: IC50 = 1.03 μM) and in vitro enzyme activities (PARP-1: IC50 = 0.40 μM; FTase: IC50 = 0.067 μM). Molecular docking and point mutation assays demonstrated the interaction of compound T9 with key amino acid residues. The compound T9 exhibited potent anti-proliferation and anti-migration capabilities against A549 and A549/5-Fu cells. PCR array and western blot results showed that compound T9 could effectively inhibit EMT-related proteins in A549 and A549/5-Fu cells, thereby inhibiting the development of lung cancer. Importantly, compound T9 could significantly inhibit tumor growth in the A549 xenograft tumor model (TGI = 65.3 %). In conclusion, this study was the first presentation of the concept of dual-target inhibitors of the PARP-1/FTase enzymes. It also provides the basis for further research and development of novel PARP-1/FTase inhibitors.
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Affiliation(s)
- Ling Yu
- Department of Pharmacy, Anorectal Hospital of Chengde Medical University, Chengde 067000, PR China
| | - You-de Wang
- Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Hebei Key Laboratory of Nerve Injury and Repair, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, PR China
| | - Zhi-Wei Yan
- Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Hebei Key Laboratory of Nerve Injury and Repair, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, PR China
| | - Li-Ying Zhang
- Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Hebei Key Laboratory of Nerve Injury and Repair, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, PR China
| | - Shuai Li
- Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Hebei Key Laboratory of Nerve Injury and Repair, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, PR China.
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38
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McCarthy KA, Marcotte DJ, Parelkar S, McKinnon CL, Trammell LE, Stangeland EL, Jetson RR. Discovery of Potent Isoindolinone Inhibitors that Target an Active Conformation of PARP1 Using DNA-Encoded Libraries. ChemMedChem 2024; 19:e202400093. [PMID: 38482564 DOI: 10.1002/cmdc.202400093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Indexed: 04/11/2024]
Abstract
Inhibition of poly (ADP-ribose) polymerase-1 (PARP1), a DNA repair enzyme, has proven to be a successful strategy for the treatment of various cancers. With the appropriate selection conditions and protein design, DNA-encoded library (DEL) technology provides a powerful avenue to identify small molecules with the desired mechanism of action towards a target of interest. However, DNA-binding proteins, such as PARP1, can be challenging targets for DEL screening due to non-specific protein-DNA interactions. To overcome this, we designed and screened a PARP1 catalytic domain construct without the autoinhibitory helical domain. This allowed us to interrogate an active, functionally-relevant form of the protein resulting in the discovery of novel isoindolinone PARP1 inhibitors with single-digit nanomolar potency. These inhibitors also demonstrated little to no PARP1-DNA trapping, a property that could be advantageous in the clinic.
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Affiliation(s)
- Kelly A McCarthy
- Discovery Sciences, Valo Health, 75 Hayden Avenue, Lexington, MA, 02421, United States
| | - Douglas J Marcotte
- Discovery Sciences, Valo Health, 75 Hayden Avenue, Lexington, MA, 02421, United States
| | - Sangram Parelkar
- Discovery Sciences, Valo Health, 75 Hayden Avenue, Lexington, MA, 02421, United States
| | - Crystal L McKinnon
- Discovery Sciences, Valo Health, 75 Hayden Avenue, Lexington, MA, 02421, United States
| | - Lindsay E Trammell
- Discovery Sciences, Valo Health, 75 Hayden Avenue, Lexington, MA, 02421, United States
| | - Eric L Stangeland
- Discovery Sciences, Valo Health, 75 Hayden Avenue, Lexington, MA, 02421, United States
| | - Rachael R Jetson
- Discovery Sciences, Valo Health, 75 Hayden Avenue, Lexington, MA, 02421, United States
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39
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Zeng H, Zhang S, Nie H, Li J, Yang J, Zhuang Y, Huang Y, Zeng M. Identification of FTY720 and COH29 as novel topoisomerase I catalytic inhibitors by experimental and computational studies. Bioorg Chem 2024; 147:107412. [PMID: 38696845 DOI: 10.1016/j.bioorg.2024.107412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Revised: 04/17/2024] [Accepted: 04/27/2024] [Indexed: 05/04/2024]
Abstract
The development of novel topoisomerase I (TOP1) inhibitors is crucial for overcoming the drawbacks and limitations of current TOP1 poisons. Here, we identified two potential TOP1 inhibitors, namely, FTY720 (a sphingosine 1-phosphate antagonist) and COH29 (a ribonucleotide reductase inhibitor), through experimental screening of known active compounds. Biological experiments verified that FTY720 and COH29 were nonintercalative TOP1 catalytic inhibitors that did not induce the formation of DNA-TOP1 covalent complexes. Molecular docking revealed that FTY720 and COH29 interacted favorably with TOP1. Molecular dynamics simulations revealed that FTY720 and COH29 could affect the catalytic domain of TOP1, thus resulting in altered DNA-binding cavity size. The alanine scanning and interaction entropy identified Arg536 as a hotspot residue. In addition, the bioinformatics analysis predicted that FTY720 and COH29 could be effective in treating malignant breast tumors. Biological experiments verified their antitumor activities using MCF-7 breast cancer cells. Their combinatory effects with TOP1 poisons were also investigated. Further, FTY720 and COH29 were found to cause less DNA damage compared with TOP1 poisons. The findings provide reliable lead compounds for the development of novel TOP1 catalytic inhibitors and offer new insights into the potential clinical applications of FTY720 and COH29 in targeting TOP1.
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Affiliation(s)
- Huang Zeng
- Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China.
| | - Shengyuan Zhang
- Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China
| | - Hua Nie
- Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China
| | - Junhao Li
- Department of Physics and Astronomy, Uppsala University, Lägerhyddsvägen 1, SE-75121 Uppsala, Sweden
| | - Jiunlong Yang
- Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China
| | - Yuanbei Zhuang
- Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China
| | - Yingjie Huang
- Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China
| | - Miao Zeng
- Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China
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40
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Luo JM, Lin HB, Weng YQ, Lin YH, Lai LY, Li J, Li FX, Xu SY, Zhang HF, Zhao W. Inhibition of PARP1 improves cardiac function after myocardial infarction via up-regulated NLRC5. Chem Biol Interact 2024; 395:111010. [PMID: 38679114 DOI: 10.1016/j.cbi.2024.111010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 03/30/2024] [Accepted: 04/18/2024] [Indexed: 05/01/2024]
Abstract
The incidence and mortality rate of myocardial infarction are increasing per year in China. The polarization of macrophages towards the classically activated macrophages (M1) phenotype is of utmost importance in the progression of inflammatory stress subsequent to myocardial infarction. Poly (ADP-ribose) polymerase 1(PARP1) is the ubiquitous and best characterized member of the PARP family, which has been reported to support macrophage polarization towards the pro-inflammatory phenotype. Yet, the role of PARP1 in myocardial ischemic injury remains to be elucidated. Here, we demonstrated that a myocardial infarction mouse model induced cardiac damage characterized by cardiac dysfunction and increased PARP1 expression in cardiac macrophages. Inhibition of PARP1 by the PJ34 inhibitors could effectively alleviate M1 macrophage polarization, reduce infarction size, decrease inflammation and rescue the cardiac function post-MI in mice. Mechanistically, the suppression of PARP1 increase NLRC5 gene expression, and thus inhibits the NF-κB pathway, thereby decreasing the production of inflammatory cytokines such as IL-1β and TNF-α. Inhibition of NLRC5 promote infection by effectively abolishing the influence of this mechanism discussed above. Interestingly, inhibition of NLRC5 promotes cardiac macrophage polarization toward an M1 phenotype but without having major effects on M2 macrophages. Our results demonstrate that inhibition of PARP1 increased NLRC5 gene expression, thereby suppressing M1 polarization, improving cardiac function, decreasing infarct area and attenuating inflammatory injury. The aforementioned findings provide new insights into the proinflammatory mechanisms that drive macrophage polarization following myocardial infarction, thereby introducing novel potential targets for future therapeutic interventions in individuals affected by myocardial infarction.
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Affiliation(s)
- Jia-Ming Luo
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Hong-Bin Lin
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Ya-Qian Weng
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Ying-Hui Lin
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China; Department of Anesthesiology, The First Affiliated Hospital of Shantou University Medical College, Guangdong Province, China
| | - Lu-Ying Lai
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Ji Li
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Feng-Xian Li
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Shi-Yuan Xu
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China
| | - Hong-Fei Zhang
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China.
| | - Wei Zhao
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, China.
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41
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Mubaid S, Sanchez BJ, Algehani RA, Skopenkova V, Adjibade P, Hall DT, Busque S, Lian XJ, Ashour K, Tremblay AMK, Carlile G, Gagné JP, Diaz-Gaxiola A, Khattak S, Di Marco S, Thomas DY, Poirier GG, Gallouzi IE. Tankyrase-1 regulates RBP-mediated mRNA turnover to promote muscle fiber formation. Nucleic Acids Res 2024; 52:4002-4020. [PMID: 38321934 DOI: 10.1093/nar/gkae059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 01/19/2024] [Indexed: 02/08/2024] Open
Abstract
Poly(ADP-ribosylation) (PARylation) is a post-translational modification mediated by a subset of ADP-ribosyl transferases (ARTs). Although PARylation-inhibition based therapies are considered as an avenue to combat debilitating diseases such as cancer and myopathies, the role of this modification in physiological processes such as cell differentiation remains unclear. Here, we show that Tankyrase1 (TNKS1), a PARylating ART, plays a major role in myogenesis, a vital process known to drive muscle fiber formation and regeneration. Although all bona fide PARPs are expressed in muscle cells, experiments using siRNA-mediated knockdown or pharmacological inhibition show that TNKS1 is the enzyme responsible of catalyzing PARylation during myogenesis. Via this activity, TNKS1 controls the turnover of mRNAs encoding myogenic regulatory factors such as nucleophosmin (NPM) and myogenin. TNKS1 mediates these effects by targeting RNA-binding proteins such as Human Antigen R (HuR). HuR harbors a conserved TNKS-binding motif (TBM), the mutation of which not only prevents the association of HuR with TNKS1 and its PARylation, but also precludes HuR from regulating the turnover of NPM and myogenin mRNAs as well as from promoting myogenesis. Therefore, our data uncover a new role for TNKS1 as a key modulator of RBP-mediated post-transcriptional events required for vital processes such as myogenesis.
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Affiliation(s)
- Souad Mubaid
- Dept. of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, 1160 Pine Avenue, Montreal, QC H3A 1A3, Canada
| | - Brenda Janice Sanchez
- KAUST Smart-Health Initiative (KSHI) and Biological and Environmental Science and Engineering (BESE) Division, King Abdullah University of Science and Technology (KAUST), Jeddah, Saudi Arabia
| | - Rinad A Algehani
- KAUST Smart-Health Initiative (KSHI) and Biological and Environmental Science and Engineering (BESE) Division, King Abdullah University of Science and Technology (KAUST), Jeddah, Saudi Arabia
| | - Viktoriia Skopenkova
- KAUST Smart-Health Initiative (KSHI) and Biological and Environmental Science and Engineering (BESE) Division, King Abdullah University of Science and Technology (KAUST), Jeddah, Saudi Arabia
| | - Pauline Adjibade
- Dept. of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, 1160 Pine Avenue, Montreal, QC H3A 1A3, Canada
| | - Derek T Hall
- Dept. of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, 1160 Pine Avenue, Montreal, QC H3A 1A3, Canada
| | - Sandrine Busque
- Dept. of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, 1160 Pine Avenue, Montreal, QC H3A 1A3, Canada
| | - Xian Jin Lian
- Dept. of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, 1160 Pine Avenue, Montreal, QC H3A 1A3, Canada
| | - Kholoud Ashour
- Dept. of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, 1160 Pine Avenue, Montreal, QC H3A 1A3, Canada
| | - Anne-Marie K Tremblay
- Dept. of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, 1160 Pine Avenue, Montreal, QC H3A 1A3, Canada
| | - Graeme Carlile
- Dept. of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
| | - Jean-Philippe Gagné
- Centre de recherche du CHU de Québec-Pavillon CHUL, Faculté de Médecine, Université Laval, Québec G1V 4G2, Canada
| | - Andrea Diaz-Gaxiola
- KAUST Smart-Health Initiative (KSHI) and Biological and Environmental Science and Engineering (BESE) Division, King Abdullah University of Science and Technology (KAUST), Jeddah, Saudi Arabia
| | - Shahryar Khattak
- KAUST Smart-Health Initiative (KSHI) and Biological and Environmental Science and Engineering (BESE) Division, King Abdullah University of Science and Technology (KAUST), Jeddah, Saudi Arabia
| | - Sergio Di Marco
- KAUST Smart-Health Initiative (KSHI) and Biological and Environmental Science and Engineering (BESE) Division, King Abdullah University of Science and Technology (KAUST), Jeddah, Saudi Arabia
- Dept. of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, 1160 Pine Avenue, Montreal, QC H3A 1A3, Canada
| | - David Y Thomas
- Dept. of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
| | - Guy G Poirier
- Centre de recherche du CHU de Québec-Pavillon CHUL, Faculté de Médecine, Université Laval, Québec G1V 4G2, Canada
| | - Imed-Eddine Gallouzi
- KAUST Smart-Health Initiative (KSHI) and Biological and Environmental Science and Engineering (BESE) Division, King Abdullah University of Science and Technology (KAUST), Jeddah, Saudi Arabia
- Dept. of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, 1160 Pine Avenue, Montreal, QC H3A 1A3, Canada
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Kawamoto Y, Morizane C, Komatsu Y, Kondo S, Ueno M, Kobayashi S, Furukawa M, Lee L, Satoh T, Sakai D, Ikeda M, Imaoka H, Miura A, Hatanaka Y, Yokota I, Nakamura Y, Yoshino T. Phase II trial of niraparib for BRCA-mutated biliary tract, pancreatic and other gastrointestinal cancers: NIR-B. Future Oncol 2024; 20:1901-1907. [PMID: 38629456 PMCID: PMC11497948 DOI: 10.2217/fon-2023-0348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 03/27/2024] [Indexed: 06/12/2024] Open
Abstract
Due to the widespread use of cancer genetic testing in gastrointestinal cancer, the BRCA1/2 genetic mutation has been identified in biliary tract cancer as well as pancreatic cancer. Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert their cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations, via the mechanism of synthetic lethality. The aim of this phase II NIR-B trial is to evaluate the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer or other gastrointestinal cancers with germline or somatic BRCA1/2 mutations revealed by genetic testing. The primary end point is an investigator-assessed objective response rate in each cohort.Clinical Trial Registration: jRCT2011200023 (ClinicalTrials.gov).
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Affiliation(s)
- Yasuyuki Kawamoto
- Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan
| | - Chigusa Morizane
- Department of Hepatobiliary & Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshito Komatsu
- Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan
| | - Shunsuke Kondo
- Department of Hepatobiliary & Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Makoto Ueno
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Satoshi Kobayashi
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Masayuki Furukawa
- Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Lingaku Lee
- Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Taroh Satoh
- Center for Cancer Genomics and Precision Medicine, Osaka University Hospital, Suita, Japan
| | - Daisuke Sakai
- Department of Frontier Science for Cancer & Chemotherapy, Osaka University Graduate School of Medicine, Suita, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary & Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiroshi Imaoka
- Department of Hepatobiliary & Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Arisa Miura
- Institute of Health Science Innovation for Medical Care, Hokkaido University Hospital, Sapporo, Japan
| | - Yutaka Hatanaka
- Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo, Japan
| | - Isao Yokota
- Department of Biostatistics, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Yoshiaki Nakamura
- Department of Gastroenterology & Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology & Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Department for the Promotion of Drug & Diagnostic Development, National Cancer Center Hospital East, Kashiwa, Japan
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43
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Messina C, Giunta EF, Signori A, Rebuzzi SE, Banna GL, Maniam A, Buti S, Cattrini C, Fornarini G, Bauckneht M, Greystoke A, Plummer R, Oing C, Rescigno P. Combining PARP Inhibitors and Androgen Receptor Signalling Inhibitors in Metastatic Prostate Cancer: A Quantitative Synthesis and Meta-analysis. Eur Urol Oncol 2024; 7:179-188. [PMID: 37574390 DOI: 10.1016/j.euo.2023.07.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 07/13/2023] [Accepted: 07/26/2023] [Indexed: 08/15/2023]
Abstract
CONTEXT PARP inhibitors (PARPi) are established treatments for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) deficiency after androgen receptor signalling inhibitor (ARSI) failure. New PARPi + ARSI combinations have been tested in all comers, although their clinical relevance in HRR-proficient tumours remains uncertain. OBJECTIVE To quantitatively synthesise evidence from randomised trials assessing the efficacy and safety of PARPi + ARSI combinations for first-line treatment of mCRPC. EVIDENCE ACQUISITION We searched the PubMed, EMBASE, SCOPUS, and Cochrane Library databases up to February 28, 2023. Randomised controlled trials (RCTs) comparing PARPi + ARSI versus placebo + ARSI for first-line treatment of mCRPC were eligible. Two reviewers independently performed screening and data extraction and assessed the risk of bias, while a third reviewer evaluated the eligibility criteria. EVIDENCE SYNTHESIS Overall, three phase 3 RCTs were included in the systematic review: PROPEL, MAGNITUDE, and TALAPRO-2. A total of 2601 patients with mCRPC were enrolled. Two of these trials (PROPEL and TALAPRO-2) assessed the radiographic progression-free survival benefit of PARPi + ARSI for first-line treatment of mCRPC, independent of HRR status. The pooled hazard ratio was 0.62 (95% confidence interval 0.53-0.72). The pooled hazard ratio for overall survival was 0.84 (95% confidence interval 0.72-0.98), indicating a 16% reduction in the risk of death among patients who received the combination. CONCLUSIONS Results from this meta-analysis support the use of ARSI + PARPi combinations in biomarker-unselected mCRPC. However, such combinations might be less clinically relevant in HRR-proficient cancers, especially considering the change in treatment landscape for mCRPC. PATIENT SUMMARY We looked at outcomes from trials testing combinations of two classes of drugs (PARP inhibitors and ARSI) in advanced prostate cancer. We found that these combinations seem to work regardless of gene mutations identified as biomarkers of response to PARP inhibitors when used on their own.
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Affiliation(s)
| | | | - Alessio Signori
- Section of Biostatistics, Department of Health Sciences, University of Genoa, Genoa, Italy
| | - Sara Elena Rebuzzi
- Medical Oncology Unit, Ospedale San Paolo, Savona, Italy; Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Giuseppe Luigi Banna
- Department of Oncology, Portsmouth Hospitals University NHS Trust, Portsmouth, UK; Faculty of Science and Health, School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK
| | - Akash Maniam
- Department of Oncology, Portsmouth Hospitals University NHS Trust, Portsmouth, UK
| | - Sebastiano Buti
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy; Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Carlo Cattrini
- SCDU Oncologia, AOU Maggiore della Carità, Novara, Italy
| | - Giuseppe Fornarini
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Matteo Bauckneht
- Section of Biostatistics, Department of Health Sciences, University of Genoa, Genoa, Italy; Nuclear Medicine, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Alastair Greystoke
- Translational and Clinical Research Institute, Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Ruth Plummer
- Translational and Clinical Research Institute, Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Christoph Oing
- Translational and Clinical Research Institute, Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK; Mildred Scheel Cancer Career Centre HaTriCS4, University Cancer Centre Hamburg, University Medical Centre Eppendorf, Hamburg, Germany
| | - Pasquale Rescigno
- Translational and Clinical Research Institute, Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK; Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy.
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44
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Besse B, Pons-Tostivint E, Park K, Hartl S, Forde PM, Hochmair MJ, Awad MM, Thomas M, Goss G, Wheatley-Price P, Shepherd FA, Florescu M, Cheema P, Chu QSC, Kim SW, Morgensztern D, Johnson ML, Cousin S, Kim DW, Moskovitz MT, Vicente D, Aronson B, Hobson R, Ambrose HJ, Khosla S, Reddy A, Russell DL, Keddar MR, Conway JP, Barrett JC, Dean E, Kumar R, Dressman M, Jewsbury PJ, Iyer S, Barry ST, Cosaert J, Heymach JV. Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial. Nat Med 2024; 30:716-729. [PMID: 38351187 PMCID: PMC10957481 DOI: 10.1038/s41591-024-02808-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 01/09/2024] [Indexed: 03/23/2024]
Abstract
For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8-2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1-20.3) versus 9.4 (7.5-10.6) months. Benefit with durvalumab-ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab-ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617.
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Affiliation(s)
- Benjamin Besse
- Institut Gustave Roussy, Paris-Saclay University, Villejuif, France
| | - Elvire Pons-Tostivint
- Medical Oncology, Centre Hospitalier Universitaire Nantes, Nantes University, Nantes, France
| | - Keunchil Park
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- MD Anderson Cancer Center, Houston, TX, USA
| | - Sylvia Hartl
- Ludwig Boltzmann Institute for Lung Health, Clinic Penzing, Vienna, Austria
- Sigmund Freud University, Vienna, Austria
| | - Patrick M Forde
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maximilian J Hochmair
- Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria
| | - Mark M Awad
- Dana-Farber Cancer Institute, Boston, MA, USA
| | - Michael Thomas
- Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
| | - Glenwood Goss
- The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Paul Wheatley-Price
- The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Frances A Shepherd
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Marie Florescu
- Division of Hematology Oncology, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Parneet Cheema
- William Osler Health System, University of Toronto, Toronto, Ontario, Canada
| | | | - Sang-We Kim
- Department of Oncology, Asan Medical Center, Seoul, Republic of Korea
| | - Daniel Morgensztern
- Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Melissa L Johnson
- Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN, USA
| | - Sophie Cousin
- Department of Medical Oncology, Institut Bergonié, Regional Comprehensive Cancer Center, Bordeaux, France
| | - Dong-Wan Kim
- Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea
| | - Mor T Moskovitz
- Institute of Oncology, Rambam Medical Center, Haifa, Israel
- Thoracic Cancer Service, Rabin Medical Center Davidoff Cancer Centre, Beilinson Campus, Petah Tikva, Israel
| | - David Vicente
- Department of Medical Oncology, Hospital Universitario Virgen Macarena, Seville, Spain
| | - Boaz Aronson
- Oncology Early Global Development, AstraZeneca, Gaithersburg, MD, USA
| | | | - Helen J Ambrose
- Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Sajan Khosla
- Real-World Evidence, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Avinash Reddy
- Oncology Data Science, Oncology R&D, AstraZeneca, Boston, MA, USA
| | - Deanna L Russell
- Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA
| | - Mohamed Reda Keddar
- Oncology Data Science, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK
| | - James P Conway
- Oncology Data Science, Oncology R&D, AstraZeneca, Gaithersburg, MD, USA
| | - J Carl Barrett
- Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA
| | - Emma Dean
- Oncology R&D, AstraZeneca, Cambridge, UK
| | - Rakesh Kumar
- Oncology R&D, AstraZeneca, Gaithersburg, MD, USA
| | | | | | - Sonia Iyer
- Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA
| | | | | | - John V Heymach
- Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
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Marcazzan S, Braz Carvalho MJ, Nguyen NT, Strangmann J, Slotta-Huspenina J, Tenditnaya A, Tschurtschenthaler M, Rieder J, Proaño-Vasco A, Ntziachristos V, Steiger K, Gorpas D, Quante M, Kossatz S. PARP1-targeted fluorescence molecular endoscopy as novel tool for early detection of esophageal dysplasia and adenocarcinoma. J Exp Clin Cancer Res 2024; 43:53. [PMID: 38383387 PMCID: PMC10880256 DOI: 10.1186/s13046-024-02963-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 01/22/2024] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND Esophageal cancer is one of the 10 most common cancers worldwide and its incidence is dramatically increasing. Despite some improvements, the current surveillance protocol with white light endoscopy and random untargeted biopsies collection (Seattle protocol) fails to diagnose dysplastic and cancerous lesions in up to 50% of patients. Therefore, new endoscopic imaging technologies in combination with tumor-specific molecular probes are needed to improve early detection. Herein, we investigated the use of the fluorescent Poly (ADP-ribose) Polymerase 1 (PARP1)-inhibitor PARPi-FL for early detection of dysplastic lesions in patient-derived organoids and transgenic mouse models, which closely mimic the transformation from non-malignant Barrett's Esophagus (BE) to invasive esophageal adenocarcinoma (EAC). METHODS We determined PARP1 expression via immunohistochemistry (IHC) in human biospecimens and mouse tissues. We also assessed PARPi-FL uptake in patient- and mouse-derived organoids. Following intravenous injection of 75 nmol PARPi-FL/mouse in L2-IL1B (n = 4) and L2-IL1B/IL8Tg mice (n = 12), we conducted fluorescence molecular endoscopy (FME) and/or imaged whole excised stomachs to assess PARPi-FL accumulation in dysplastic lesions. L2-IL1B/IL8Tg mice (n = 3) and wild-type (WT) mice (n = 2) without PARPi-FL injection served as controls. The imaging results were validated by confocal microscopy and IHC of excised tissues. RESULTS IHC on patient and murine tissue revealed similar patterns of increasing PARP1 expression in presence of dysplasia and cancer. In human and murine organoids, PARPi-FL localized to PARP1-expressing epithelial cell nuclei after 10 min of incubation. Injection of PARPi-FL in transgenic mouse models of BE resulted in the successful detection of lesions via FME, with a mean target-to-background ratio > 2 independently from the disease stage. The localization of PARPi-FL in the lesions was confirmed by imaging of the excised stomachs and confocal microscopy. Without PARPi-FL injection, identification of lesions via FME in transgenic mice was not possible. CONCLUSION PARPi-FL imaging is a promising approach for clinically needed improved detection of dysplastic and malignant EAC lesions in patients with BE. Since PARPi-FL is currently evaluated in a phase 2 clinical trial for oral cancer detection after topical application, clinical translation for early detection of dysplasia and EAC in BE patients via FME screening appears feasible.
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Affiliation(s)
- Sabrina Marcazzan
- II. Medizinische Klinik, TUM School of Medicine and Health, Klinikum Rechts der Isar at Technical University of Munich, Munich, 81675, Germany
- Institute of Biological and Medical Imaging, Helmholtz Zentrum München, 85764 Neuherberg, Germany and Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany
- Clinical Radiology, Medical School OWL, Bielefeld University, Bielefeld, 33615, Germany
| | - Marcos J Braz Carvalho
- II. Medizinische Klinik, TUM School of Medicine and Health, Klinikum Rechts der Isar at Technical University of Munich, Munich, 81675, Germany
| | - Nghia T Nguyen
- Department of Nuclear Medicine, TUM School of Medicine and Health, Klinikum Rechts der Isar at Technical University of Munich, Munich, 81675, Germany
- Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany
| | - Julia Strangmann
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany
| | - Julia Slotta-Huspenina
- Institute of Pathology, TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany
| | - Anna Tenditnaya
- Institute of Biological and Medical Imaging, Helmholtz Zentrum München, 85764 Neuherberg, Germany and Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany
| | - Markus Tschurtschenthaler
- Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, 69120, Germany
- Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, TUM School of Medicine and Health, Klinikum rechts der Isar at Technical University of Munich, Munich, 81675, Germany
| | - Jonas Rieder
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany
| | - Andrea Proaño-Vasco
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany
| | - Vasilis Ntziachristos
- Institute of Biological and Medical Imaging, Helmholtz Zentrum München, 85764 Neuherberg, Germany and Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany
| | - Katja Steiger
- Institute of Pathology, TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany
- Comparative Experimental Pathology (CEP) and IBioTUM tissue biobank, TUM School of Medicine and Health, Technical University of Munich, München, 81675, Germany
| | - Dimitris Gorpas
- Institute of Biological and Medical Imaging, Helmholtz Zentrum München, 85764 Neuherberg, Germany and Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany
| | - Michael Quante
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany.
| | - Susanne Kossatz
- Department of Nuclear Medicine, TUM School of Medicine and Health, Klinikum Rechts der Isar at Technical University of Munich, Munich, 81675, Germany.
- Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany.
- Department of Chemistry, TUM School of Natural Sciences, Technical University of Munich, Munich, 85748, Germany.
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Zhang Z, Rondon-Cordero HM, Das C. Crystal structure of bacterial ubiquitin ADP-ribosyltransferase CteC reveals a substrate-recruiting insertion. J Biol Chem 2024; 300:105604. [PMID: 38159861 PMCID: PMC10810742 DOI: 10.1016/j.jbc.2023.105604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 12/18/2023] [Accepted: 12/21/2023] [Indexed: 01/03/2024] Open
Abstract
ADP-ribosylation is a post-translational modification involved in regulation of diverse cellular pathways. Interestingly, many pathogens have been identified to utilize ADP-ribosylation as a way for host manipulation. A recent study found that CteC, an effector from the bacterial pathogen Chromobacterium violaceum, hinders host ubiquitin (Ub) signaling pathways via installing mono-ADP-ribosylation on threonine 66 of Ub. However, the molecular basis of substrate recognition by CteC is not well understood. In this article, we probed the substrate specificity of this effector at protein and residue levels. We also determined the crystal structure of CteC in complex with NAD+, which revealed a canonical mono-ADP-ribosyltransferase fold with an additional insertion domain. The AlphaFold-predicted model differed significantly from the experimentally determined structure, even in regions not used in crystal packing. Biochemical and biophysical studies indicated unique features of the NAD+ binding pocket, while showing selectivity distinction between Ub and structurally close Ub-like modifiers and the role of the insertion domain in substrate recognition. Together, this study provides insights into the enzymatic specificities and the key structural features of a novel bacterial ADP-ribosyltransferase involved in host-pathogen interaction.
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Affiliation(s)
- Zhengrui Zhang
- Department of Chemistry, Purdue University, West Lafayette, Indiana, USA
| | | | - Chittaranjan Das
- Department of Chemistry, Purdue University, West Lafayette, Indiana, USA.
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Tan Y, Song Q. Bibliometric analysis of research trends on the combination of immune checkpoint inhibitors and PARP inhibitors in solid tumors. Heliyon 2024; 10:e24452. [PMID: 38293546 PMCID: PMC10826821 DOI: 10.1016/j.heliyon.2024.e24452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 12/13/2023] [Accepted: 01/09/2024] [Indexed: 02/01/2024] Open
Abstract
Introduction Immune checkpoint inhibitors (ICIs) has made significant achievements in the therapeutics of various tumor types, and recently growing evidence from preclinical studies and clinical trials has indicated that poly-ADP-ribose polymerase inhibitors (PARPi) are exhibiting encouraging synergism with ICIs. The aim of our current study is to explore the development pattern of literature related to the combined therapy of ICIs and PARPi in solid tumors from a bibliometric perspective. Methods Publications concerning the combination of ICIs and PARPi in solid tumors during 2008-2022 were extracted from the WOSCC database. VOSviewer and R-bibliometrix were applied to conduct bibliometrics. Results In total, 1113 articles were finally included. The USA was the most dominant country, and University of Texas MD Anderson Cancer Center was the most fruitful institute. Andreas Schneeweiss ranked first concerning the amount of publications in this research domain, and Timothy Yap had the most citations on this theme. The analysis of keyword co-occurrence indicated that research frontiers were shifted from the biological mechanisms of cell death to the combined strategy of ICIs and PARPi in clinical trials. Conclusions Our study comprehensively examined the publications on the combination of ICIs and PARPi in solid tumors from a bibliometric perspective. The research on this topic is in its rapid growth stage, and the USA is possessing an absolutely leading position in this field by its scientific accumulations and productivity. Moreover, the research frontiers have shifted from the mechanisms of ICIs and PARPi to their combined treatment in clinical application. In summary, our results demonstrated a comprehensive overview of the knowledge atlas and a valuable reference for the future investigations in this field.
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Affiliation(s)
- Yaqian Tan
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qi Song
- Department of Pharmacy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
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De Mel S, Lee AR, Tan JHI, Tan RZY, Poon LM, Chan E, Lee J, Chee YL, Lakshminarasappa SR, Jaynes PW, Jeyasekharan AD. Targeting the DNA damage response in hematological malignancies. Front Oncol 2024; 14:1307839. [PMID: 38347838 PMCID: PMC10859481 DOI: 10.3389/fonc.2024.1307839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 01/03/2024] [Indexed: 02/15/2024] Open
Abstract
Deregulation of the DNA damage response (DDR) plays a critical role in the pathogenesis and progression of many cancers. The dependency of certain cancers on DDR pathways has enabled exploitation of such through synthetically lethal relationships e.g., Poly ADP-Ribose Polymerase (PARP) inhibitors for BRCA deficient ovarian cancers. Though lagging behind that of solid cancers, DDR inhibitors (DDRi) are being clinically developed for haematological cancers. Furthermore, a high proliferative index characterize many such cancers, suggesting a rationale for combinatorial strategies targeting DDR and replicative stress. In this review, we summarize pre-clinical and clinical data on DDR inhibition in haematological malignancies and highlight distinct haematological cancer subtypes with activity of DDR agents as single agents or in combination with chemotherapeutics and targeted agents. We aim to provide a framework to guide the design of future clinical trials involving haematological cancers for this important class of drugs.
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Affiliation(s)
- Sanjay De Mel
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Ainsley Ryan Lee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Joelle Hwee Inn Tan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Rachel Zi Yi Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Li Mei Poon
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Esther Chan
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Joanne Lee
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Yen Lin Chee
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Satish R. Lakshminarasappa
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Patrick William Jaynes
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Anand D. Jeyasekharan
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
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Yi W, Hu M, Shi L, Li T, Bai C, Sun F, Ma H, Zhao Z, Yan S. Whole genome sequencing identified genomic diversity and candidated genes associated with economic traits in Northeasern Merino in China. Front Genet 2024; 15:1302222. [PMID: 38333624 PMCID: PMC10851152 DOI: 10.3389/fgene.2024.1302222] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 01/12/2024] [Indexed: 02/10/2024] Open
Abstract
Introduction: Northeast Merino (NMS) is a breed developed in Northeast China during the 1960s for wool and meat production. It exhibits excellent traits such as high wool yield, superior meat quality, rapid growth rate, robust disease resistance, and adaptability to cold climates. However, no studies have used whole-genome sequencing data to investigate the superior traits of NMS. Methods: In this study, we investigated the population structure, genetic diversity, and selection signals of NMS using whole-genome sequencing data from 20 individuals. Two methods (integrated haplotype score and composite likelihood ratio) were used for selection signal analysis, and the Fixation Index was used to explore the selection signals of NMS and the other two breeds, Mongolian sheep and South African meat Merino. Results: The results showed that NMS had low inbreeding levels, high genomic diversity, and a pedigree of both Merino breeds and Chinese local breeds. A total length of 14.09 Mb genomic region containing 287 genes was detected using the two methods. Further exploration of the functions of these genes revealed that they are mainly concentrated in wool production performance (IRF2BP2, MAP3K7, and WNT3), meat production performance (NDUFA9, SETBP1, ZBTB38, and FTO), cold resistance (DNAJC13, LPGAT1, and PRDM16), and immune response (PRDM2, GALNT8, and HCAR2). The selection signals of NMS and the other two breeds annotated 87 and 23 genes, respectively. These genes were also mainly focused on wool and meat production performance. Conclusion: These results provide a basis for further breeding improvement, comprehensive use of this breed, and a reference for research on other breeds.
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Affiliation(s)
- Wenfeng Yi
- College of Animal Science, Jilin University, Changchun, China
| | - Mingyue Hu
- College of Animal Science, Jilin University, Changchun, China
| | - Lulu Shi
- College of Animal Science, Jilin University, Changchun, China
| | - Ting Li
- College of Animal Science, Jilin University, Changchun, China
| | - Chunyan Bai
- College of Animal Science, Jilin University, Changchun, China
| | - Fuliang Sun
- College of Agriculture, Yanbian University, Yanji, China
| | - Huihai Ma
- Institute of Animal Husbandry and Veterinary, Jilin Academy of Agricultural Sciences, Gongzhuling, China
| | - Zhongli Zhao
- Institute of Animal Husbandry and Veterinary, Jilin Academy of Agricultural Sciences, Gongzhuling, China
| | - Shouqing Yan
- College of Animal Science, Jilin University, Changchun, China
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50
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Kim C, Wang XD, Liu Z, Hao J, Wang S, Li P, Zi Z, Ding Q, Jang S, Kim J, Luo Y, Huffman KE, Pal Choudhuri S, del Rio S, Cai L, Liang H, Drapkin BJ, Minna JD, Yu Y. Induced degradation of lineage-specific oncoproteins drives the therapeutic vulnerability of small cell lung cancer to PARP inhibitors. SCIENCE ADVANCES 2024; 10:eadh2579. [PMID: 38241363 PMCID: PMC10798557 DOI: 10.1126/sciadv.adh2579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 12/20/2023] [Indexed: 01/21/2024]
Abstract
Although BRCA1/2 mutations are not commonly found in small cell lung cancer (SCLC), a substantial fraction of SCLC shows clinically relevant response to PARP inhibitors (PARPis). However, the underlying mechanism(s) of PARPi sensitivity in SCLC is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in SCLC cells. We found that the vulnerability of SCLC to PARPi could be explained by the degradation of lineage-specific oncoproteins (e.g., ASCL1). PARPi-induced activation of the E3 ligase HUWE1 mediated the ubiquitin-proteasome system (UPS)-dependent ASCL1 degradation. Although PARPi induced a general DNA damage response in SCLC cells, this signal generated a cell-specific response in ASCL1 degradation, leading to the identification of HUWE1 expression as a predictive biomarker for PARPi. Combining PARPi with agents targeting these pathways markedly improved therapeutic response in SCLC. The degradation of lineage-specific oncoproteins therefore represents a previously unidentified mechanism for PARPi efficacy in SCLC.
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Affiliation(s)
- Chiho Kim
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| | - Xu-Dong Wang
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| | - Zhengshuai Liu
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| | - Jianwei Hao
- Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| | - Shuai Wang
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Peng Li
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Zhenzhen Zi
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Qing Ding
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Seoyeon Jang
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jiwoong Kim
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yikai Luo
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kenneth E. Huffman
- Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Shreoshi Pal Choudhuri
- Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sofia del Rio
- Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| | - Ling Cai
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Han Liang
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Benjamin J. Drapkin
- Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - John D. Minna
- Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yonghao Yu
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
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