|
1
|
Wei Z, Su L, Gao S. The roles of ubiquitination in AML. Ann Hematol 2024; 103:3413-3428. [PMID: 37603061 DOI: 10.1007/s00277-023-05415-y] [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: 04/25/2023] [Accepted: 08/10/2023] [Indexed: 08/22/2023]
Abstract
Acute myeloid leukemia (AML) is a heterogeneously malignant disorder resulting in poor prognosis. Ubiquitination, a major post-translational modification (PTM), plays an essential role in regulating various cellular processes and determining cell fate. Despite these initial insights, the precise role of ubiquitination in AML pathogenesis and treatment remains largely unknown. In order to address this knowledge gap, we explore the relationship between ubiquitination and AML from the perspectives of signal transduction, cell differentiation, and cell cycle control; and try to find out how this relationship can be utilized to inform new therapeutic strategies for AML patients.
Collapse
Affiliation(s)
- Zhifeng Wei
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
| | - Long Su
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
| | - Sujun Gao
- Department of Hematology, The First Hospital of Jilin University, Changchun, China.
| |
Collapse
|
|
2
|
Wang W, Albadari N, Du Y, Fowler JF, Sang HT, Xian W, McKeon F, Li W, Zhou J, Zhang R. MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future. Pharmacol Rev 2024; 76:414-453. [PMID: 38697854 PMCID: PMC11068841 DOI: 10.1124/pharmrev.123.001026] [Citation(s) in RCA: 39] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 11/28/2023] [Accepted: 01/16/2024] [Indexed: 05/05/2024] Open
Abstract
Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are several current clinical trials of promising agents that may overcome the past failures, including agents granted FDA orphan drug or fast-track status. We herein summarize the research efforts to discover and develop MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of the p53 status of the cancer. We also describe how preclinical and clinical investigations have moved toward combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. Finally, we discuss the current challenges and future directions to accelerate the clinical application of MDM2 inhibitors. In conclusion, targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of the existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to finally realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 has been implicated. SIGNIFICANCE STATEMENT: Overexpression/amplification of the MDM2 oncogene has been detected in various human cancers and is associated with disease progression, treatment resistance, and poor patient outcomes. This article reviews the previous, current, and emerging MDM2-targeted therapies and summarizes the preclinical and clinical studies combining MDM2 inhibitors with chemotherapy and immunotherapy regimens. The findings of these contemporary studies may lead to safer and more effective treatments for patients with cancers overexpressing MDM2.
Collapse
Affiliation(s)
- Wei Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Najah Albadari
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Yi Du
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Josef F Fowler
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Hannah T Sang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Wa Xian
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Frank McKeon
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Wei Li
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Jia Zhou
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Ruiwen Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| |
Collapse
|
|
3
|
Zawacka JE. p53 biology and reactivation for improved therapy in MDS and AML. Biomark Res 2024; 12:34. [PMID: 38481290 PMCID: PMC10936007 DOI: 10.1186/s40364-024-00579-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 03/01/2024] [Indexed: 11/02/2024] Open
Abstract
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) originate from preleukemic hematopoietic conditions, such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenia of undetermined significance (CCUS) and have variable outcomes despite the successful implementation of targeted therapies. The prognosis differs depending on the molecular subgroup. In patients with TP53 mutations, the most inferior outcomes across independent studies were observed. Myeloid malignancies with TP53 mutations have complex cytogenetics and extensive structural variants. These factors contribute to worse responses to induction therapy, demethylating agents, or venetoclax-based treatments. Survival of patients with biallelic TP53 gene mutations is often less than one year but this depends on the type of treatment applied. It is still controversial whether the allelic state of mutant TP53 impacts the outcomes in patients with AML and high-risk MDS. Further studies are needed to justify estimating TP53 LOH status for better risk assessment. Yet, TP53-mutated MDS, MDS/AML and AML are now classified separately in the International Consensus Classification (ICC). In the clinical setting, the wild-type p53 protein is reactivated pharmacologically by targeting p53/MDM2/MDM4 interactions and mutant p53 reactivation is achieved by refolding the DNA binding domain to wild-type-like conformation or via targeted degradation of the mutated protein. This review discusses our current understanding of p53 biology in MDS and AML and the promises and failures of wild-type and mutant p53 reactivation in the clinical trial setting.
Collapse
Affiliation(s)
- Joanna E Zawacka
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
- Department of Biochemistry, Laboratory of Biophysics and p53 Protein Biology, Medical University of Warsaw, Warsaw, Poland.
| |
Collapse
|
|
4
|
Senapati J, Muftuoglu M, Ishizawa J, Abbas HA, Loghavi S, Borthakur G, Yilmaz M, Issa GC, Dara SI, Basyal M, Li L, Naqvi K, Pourebrahim R, Jabbour EJ, Kornblau SM, Short NJ, Pemmaraju N, Garcia-Manero G, Ravandi F, Khoury J, Daver N, Kantarjian HM, Andreeff M, DiNardo CD. A Phase I study of Milademetan (DS3032b) in combination with low dose cytarabine with or without venetoclax in acute myeloid leukemia: Clinical safety, efficacy, and correlative analysis. Blood Cancer J 2023; 13:101. [PMID: 37386016 PMCID: PMC10310786 DOI: 10.1038/s41408-023-00871-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/02/2023] [Accepted: 06/13/2023] [Indexed: 07/01/2023] Open
Abstract
In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, the p53-MDM2 axis and the interplay between pro/anti-apoptotic molecules to identify factors that determine response and resistance to therapy. Sixteen patients (14 R/R, 2 N/D treated secondary AML) at a median age of 70 years (range, 23-80 years) were treated in this trial. Two patients (13%) achieved an overall response (complete remission with incomplete hematological recovery). Median cycles on trial were 1 (range 1-7) and at a median follow-up of 11 months, no patients remained on active therapy. Gastrointestinal toxicity was significant and dose-limiting (50% of patients ≥ grade 3). Single-cell proteomic analysis of the leukemia compartment revealed therapy-induced proteomic alterations and potential mechanisms of adaptive response to the MDM2i combination. The response was associated with immune cell abundance and induced the proteomic profiles of leukemia cells to disrupt survival pathways and significantly reduced MCL1 and YTHDF2 to potentiate leukemic cell death. The combination of milademetan, LDAC±venetoclax led to only modest responses with recognizable gastrointestinal toxicity. Treatment-induced reduction of MCL1 and YTHDF2 in an immune-rich milieu correlate with treatment response.
Collapse
Affiliation(s)
- Jayastu Senapati
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Jo Ishizawa
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Hussein A Abbas
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Sanam Loghavi
- Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA
| | - Gautam Borthakur
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Musa Yilmaz
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Ghayas C Issa
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Samuel I Dara
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Mahesh Basyal
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Li Li
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Kiran Naqvi
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Elias J Jabbour
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Nicholas J Short
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Naveen Pemmaraju
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Farhad Ravandi
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | - Joseph Khoury
- Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA
| | - Naval Daver
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Michael Andreeff
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
| | | |
Collapse
|
|
5
|
Yi J, Tavana O, Li H, Wang D, Baer RJ, Gu W. Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy. Nat Commun 2023; 14:1941. [PMID: 37024504 PMCID: PMC10079682 DOI: 10.1038/s41467-023-37617-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 03/24/2023] [Indexed: 04/08/2023] Open
Abstract
Since Mdm2 (Mouse double minute 2) inhibitors show serious toxicity in clinic studies, different approaches to achieve therapeutic reactivation of p53-mediated tumor suppression in cancers need to be explored. Here, we identify the USP2 (ubiquitin specific peptidase 2)-VPRBP (viral protein R binding protein) axis as an important pathway for p53 regulation. Like Mdm2, VPRBP is a potent repressor of p53 but VPRBP stability is controlled by USP2. Interestingly, the USP2-VPRBP axis also regulates PD-L1 (programmed death-ligand 1) expression. Strikingly, the combination of a small-molecule USP2 inhibitor and anti-PD1 monoclonal antibody leads to complete regression of the tumors expressing wild-type p53. In contrast to Mdm2, knockout of Usp2 in mice has no obvious effect in normal tissues. Moreover, no obvious toxicity is observed upon the USP2 inhibitor treatment in vivo as Mdm2-mediated regulation of p53 remains intact. Our study reveals a promising strategy for p53-based therapy by circumventing the toxicity issue.
Collapse
Affiliation(s)
- Jingjie Yi
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY, 10032, USA
| | - Omid Tavana
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY, 10032, USA
| | - Huan Li
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY, 10032, USA
| | - Donglai Wang
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY, 10032, USA
| | - Richard J Baer
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY, 10032, USA
- Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY, 10032, USA
| | - Wei Gu
- Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY, 10032, USA.
- Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY, 10032, USA.
| |
Collapse
|
|
6
|
Ming H, Li B, Jiang J, Qin S, Nice EC, He W, Lang T, Huang C. Protein degradation: expanding the toolbox to restrain cancer drug resistance. J Hematol Oncol 2023; 16:6. [PMID: 36694209 PMCID: PMC9872387 DOI: 10.1186/s13045-023-01398-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 01/01/2023] [Indexed: 01/25/2023] Open
Abstract
Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib and proteolysis-targeting chimeric have been developed. Compared with intervention at the transcriptional level, targeting the degradation process seems to be a more rapid and direct strategy. Proteasomal proteolysis and lysosomal proteolysis are the most critical quality control systems responsible for the degradation of proteins or organelles. Although proteasomal and lysosomal inhibitors (e.g., bortezomib and chloroquine) have achieved certain improvements in some clinical application scenarios, their routine application in practice is still a long way off, which is due to the lack of precise targeting capabilities and inevitable side effects. In-depth studies on the regulatory mechanism of critical protein degradation regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones, are expected to provide precise clues for developing targeting strategies and reducing side effects. Here, we discuss the underlying mechanisms of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling to delineate the functional roles of protein degradation in drug resistance. We also highlight specific E3 ligases, DUBs, and chaperones, discussing possible strategies modulating protein degradation to target cancer drug resistance. A systematic summary of the molecular basis by which protein degradation regulates tumor drug resistance will help facilitate the development of appropriate clinical strategies.
Collapse
Affiliation(s)
- Hui Ming
- West China School of Basic Medical Sciences and Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Bowen Li
- West China School of Basic Medical Sciences and Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Jingwen Jiang
- West China School of Basic Medical Sciences and Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Siyuan Qin
- West China School of Basic Medical Sciences and Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia
| | - Weifeng He
- Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Army Military Medical University, Chongqing, 400038, China.
| | - Tingyuan Lang
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, 400030, People's Republic of China. .,Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, People's Republic of China.
| | - Canhua Huang
- West China School of Basic Medical Sciences and Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China.
| |
Collapse
|
|
7
|
Recent advances in the pharmacological targeting of ubiquitin-regulating enzymes in cancer. Semin Cell Dev Biol 2022; 132:213-229. [PMID: 35184940 DOI: 10.1016/j.semcdb.2022.02.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 02/04/2022] [Accepted: 02/07/2022] [Indexed: 12/15/2022]
Abstract
As a post-translational modification that has pivotal roles in protein degradation, ubiquitination ensures that intracellular proteins act in a precise spatial and temporal manner to regulate diversified cellular processes. Perturbation of the ubiquitin system contributes directly to the onset and progression of a wide variety of diseases, including various subtypes of cancer. This highly regulated system has been for years an active research area for drug discovery that is exemplified by several approved drugs. In this review, we will provide an update of the main breakthrough scientific discoveries that have been leading the clinical development of ubiquitin-targeting therapies in the last decade, with a special focus on E1 and E3 modulators. We will further discuss the unique challenges of identifying new potential therapeutic targets within this ubiquitous and highly complex machinery, based on available crystallographic structures, and explore chemical approaches by which these challenges might be met.
Collapse
|
|
8
|
da Mota VHS, Freire de Melo F, de Brito BB, Silva FAFD, Teixeira KN. Molecular docking of DS-3032B, a mouse double minute 2 enzyme antagonist with potential for oncology treatment development. World J Clin Oncol 2022; 13:496-504. [PMID: 35949428 PMCID: PMC9244969 DOI: 10.5306/wjco.v13.i6.496] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/16/2021] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND It is known that p53 suppression is an important marker of poor prognosis of cancers, especially in solid tumors of the breast, lung, stomach, and esophagus; liposarcomas, glioblastomas, and leukemias. Because p53 has mouse double minute 2 (MDM2) as its primary negative regulator, this molecular docking study seeks to answer the following hypotheses: Is the interaction between DS-3032B and MDM2 stable enough for this drug to be considered as a promising neoplastic inhibitor? AIM To analyze, in silico, the chemical bonds between the antagonist DS-3032B and its binding site in MDM2. METHODS For molecular docking simulations, the file containing structures of MDM2 (receptor) and the drug DS-3032B (ligand) were selected. The three-dimensional structure of MDM2 was obtained from Protein Data Bank, and the one for DS-3032B was obtained from PubChem database. The location and dimensions of the Grid box was determined using AutoDock Tools software. In this case, the dimensions of the Grid encompassed the entire receptor. The ligand DS-3032B interacts with the MDM2 receptor in a physiological environment with pH 7.4; thus, to simulate more reliably, its interaction was made with the calculation for the prediction of its protonation state using the MarvinSketch® software. Both ligands, with and without the protonation, were prepared for molecular docking using the AutoDock Tools software. This software detects the torsion points of the drug and calculates the angle of the torsions. Molecular docking simulations were performed using the tools of the AutoDock platform connected to the Vina software. The analyses of the amino acid residues involved in the interactions between the receptor and the ligand as well as the twists of the ligand, atoms involved in the interactions, and type, strength, and length of the interactions were performed using the PyMol software (pymol.org/2) and Discovery Studio from BIOVIA®. RESULTS The global alignment indicated crystal structure 5SWK was more suitable for docking simulations by presenting the p53 binding site. The three-dimensional structure 5SWK for MDM2 was selected from Protein Data Bank and the three-dimensional structure of DS-3032B was selected from PubChem (Compound CID: 73297272; Milademetan). After molecular docking simulations, the most stable conformer was selected for both protonated and non-protonated DS-3032B. The interaction between MDM2 and DS-3032B occurs with high affinity; no significant difference was observed in the affinity energies between the MDM2/pronated DS-3032B (-9.9 kcal/mol) and MDM2/non-protonated DS-3032B conformers (-10.0 kcal/mol). Sixteen amino acid residues of MDM2 are involved in chemical bonds with the protonated DS-3032B; these 16 residues of MDM2 belong to the p53 biding site region and provide high affinity to interaction and stability to drug-protein complex. CONCLUSION Molecular docking indicated that DS-3032B antagonist binds to the same region of the p53 binding site in the MDM2 with high affinity and stability, and this suggests therapeutic efficiency.
Collapse
Affiliation(s)
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | | |
Collapse
|
|
9
|
Han X, Wei W, Sun Y. PROTAC Degraders with Ligands Recruiting MDM2 E3 Ubiquitin Ligase: An Updated Perspective. ACTA MATERIA MEDICA 2022; 1:244-259. [PMID: 35734447 PMCID: PMC9211018 DOI: 10.15212/amm-2022-0010] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase which effectively degrades tumor suppressor p53. In the past two decades, many MDM2 inhibitors that disrupt the MDM2-p53 binding have been discovered and developed. Given that the MDM2-p53 forms auto-regulatory loop in which p53 is a substrate of MDM2 for targeted degradation, while MDM2 is a p53 target for transcriptional upregulation, these MDM2 inhibitors have limited efficacy due to p53 degradation by accumulated MDM2 upon rapid in vivo clearance of the MDM2 inhibitors. Fortunately, proteolysis targeting chimeras (PROTACs), a novel therapeutic strategy, overcome the limitations of MDM2 inhibitors. Some of MDM2 inhibitors developed in the past two decades have been used in PROTAC technology for two applications: 1) as component 1 to bind with endogenous MDM2 as a target for PROTAC-based degradation of MDM2; and 2) as component 2 to bind with endogenous MDM2 as a PROTAC E3 ligand for PROTAC-based degradation of other oncogenic proteins. In this review, we summarize current progress in the discovery and development of MDM2-based PROTAC drugs with future perspectives and challenges for their applications in effective treatment of human cancer.
Collapse
Affiliation(s)
- Xin Han
- Cancer Institute of the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China
- Cancer Center, Zhejiang University, Hangzhou 310014, China
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Yi Sun
- Cancer Institute of the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China
- Cancer Center, Zhejiang University, Hangzhou 310014, China
- Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou 310053, China
| |
Collapse
|
|
10
|
Andreozzi F, Massaro F, Wittnebel S, Spilleboudt C, Lewalle P, Salaroli A. New Perspectives in Treating Acute Myeloid Leukemia: Driving towards a Patient-Tailored Strategy. Int J Mol Sci 2022; 23:3887. [PMID: 35409248 PMCID: PMC8999556 DOI: 10.3390/ijms23073887] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/27/2022] [Accepted: 03/28/2022] [Indexed: 12/16/2022] Open
Abstract
For decades, intensive chemotherapy (IC) has been considered the best therapeutic option for treating acute myeloid leukemia (AML), with no curative option available for patients who are not eligible for IC or who have had failed IC. Over the last few years, several new drugs have enriched the therapeutic arsenal of AML treatment for both fit and unfit patients, raising new opportunities but also new challenges. These include the already approved venetoclax, the IDH1/2 inhibitors enasidenib and ivosidenib, gemtuzumab ozogamicin, the liposomal daunorubicin/cytarabine formulation CPX-351, and oral azacitidine. Venetoclax, an anti BCL2-inhibitor, in combination with hypomethylating agents (HMAs), has markedly improved the management of unfit and elderly patients from the perspective of improved quality of life and better survival. Venetoclax is currently under investigation in combination with other old and new drugs in early phase trials. Recently developed drugs with different mechanisms of action and new technologies that have already been investigated in other settings (BiTE and CAR-T cells) are currently being explored in AML, and ongoing trials should determine promising agents, more synergic combinations, and better treatment strategies. Access to new drugs and inclusion in clinical trials should be strongly encouraged to provide scientific evidence and to define the future standard of treatment in AML.
Collapse
Affiliation(s)
- Fabio Andreozzi
- Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Bruxelles, Belgium; (F.M.); (S.W.); (C.S.); (P.L.); (A.S.)
| | - Fulvio Massaro
- Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Bruxelles, Belgium; (F.M.); (S.W.); (C.S.); (P.L.); (A.S.)
- PhD Program in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Sebastian Wittnebel
- Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Bruxelles, Belgium; (F.M.); (S.W.); (C.S.); (P.L.); (A.S.)
| | - Chloé Spilleboudt
- Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Bruxelles, Belgium; (F.M.); (S.W.); (C.S.); (P.L.); (A.S.)
| | - Philippe Lewalle
- Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Bruxelles, Belgium; (F.M.); (S.W.); (C.S.); (P.L.); (A.S.)
| | - Adriano Salaroli
- Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Bruxelles, Belgium; (F.M.); (S.W.); (C.S.); (P.L.); (A.S.)
| |
Collapse
|
|
11
|
Kukushkin M, Novotortsev V, Filatov V, Ivanenkov Y, Skvortsov D, Veselov M, Shafikov R, Moiseeva A, Zyk N, Majouga A, Beloglazkina E. Synthesis and Biological Evaluation of S-, O- and Se-Containing Dispirooxindoles. Molecules 2021; 26:molecules26247645. [PMID: 34946727 PMCID: PMC8703884 DOI: 10.3390/molecules26247645] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 12/06/2021] [Accepted: 12/10/2021] [Indexed: 12/12/2022] Open
Abstract
A series of novel S-, O- and Se-containing dispirooxindole derivatives has been synthesized using 1,3-dipolar cycloaddition reaction of azomethine ylide generated from isatines and sarcosine at the double C=C bond of 5-indolidene-2-chalcogen-imidazolones (chalcogen was oxygen, sulfur or selenium). The cytotoxicity of these dispiro derivatives was evaluated in vitro using different tumor cell lines. Several molecules have demonstrated a considerable cytotoxicity against the panel and showed good selectivity towards colorectal carcinoma HCT116 p53+/+ over HCT116 p53−/− cells. In particular, good results have been obtained for LNCaP prostate cell line. The performed in silico study has revealed MDM2/p53 interaction as one of the possible targets for the synthesized molecules. However, in contrast to selectivity revealed during the cell-based evaluation and the results obtained in computational study, no significant p53 activation using a reporter construction in p53wt A549 cell line was observed in a relevant concentration range.
Collapse
Affiliation(s)
- Maksim Kukushkin
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, GSP-1, 119991 Moscow, Russia; (M.K.); (V.N.); (V.F.); (D.S.); (R.S.); (A.M.); (N.Z.); (A.M.)
- Research Laboratory of Biophysics, National University of Science and Technology MISiS, 119049 Moscow, Russia
| | - Vladimir Novotortsev
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, GSP-1, 119991 Moscow, Russia; (M.K.); (V.N.); (V.F.); (D.S.); (R.S.); (A.M.); (N.Z.); (A.M.)
| | - Vadim Filatov
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, GSP-1, 119991 Moscow, Russia; (M.K.); (V.N.); (V.F.); (D.S.); (R.S.); (A.M.); (N.Z.); (A.M.)
| | - Yan Ivanenkov
- Laboratory of Medicinal Chemistry and Bioinformatic, Moscow Institute of Physics and Technology (MIPT), Institutski Pereulok 9, 141701 Dolgoprudny, Russia; (Y.I.); (M.V.)
| | - Dmitry Skvortsov
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, GSP-1, 119991 Moscow, Russia; (M.K.); (V.N.); (V.F.); (D.S.); (R.S.); (A.M.); (N.Z.); (A.M.)
| | - Mark Veselov
- Laboratory of Medicinal Chemistry and Bioinformatic, Moscow Institute of Physics and Technology (MIPT), Institutski Pereulok 9, 141701 Dolgoprudny, Russia; (Y.I.); (M.V.)
| | - Radik Shafikov
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, GSP-1, 119991 Moscow, Russia; (M.K.); (V.N.); (V.F.); (D.S.); (R.S.); (A.M.); (N.Z.); (A.M.)
| | - Anna Moiseeva
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, GSP-1, 119991 Moscow, Russia; (M.K.); (V.N.); (V.F.); (D.S.); (R.S.); (A.M.); (N.Z.); (A.M.)
| | - Nikolay Zyk
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, GSP-1, 119991 Moscow, Russia; (M.K.); (V.N.); (V.F.); (D.S.); (R.S.); (A.M.); (N.Z.); (A.M.)
| | - Alexander Majouga
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, GSP-1, 119991 Moscow, Russia; (M.K.); (V.N.); (V.F.); (D.S.); (R.S.); (A.M.); (N.Z.); (A.M.)
- Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya Sq. 9, 125047 Moscow, Russia
| | - Elena Beloglazkina
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, GSP-1, 119991 Moscow, Russia; (M.K.); (V.N.); (V.F.); (D.S.); (R.S.); (A.M.); (N.Z.); (A.M.)
- Correspondence:
| |
Collapse
|
|
12
|
Mancini F, Giorgini L, Teveroni E, Pontecorvi A, Moretti F. Role of Sex in the Therapeutic Targeting of p53 Circuitry. Front Oncol 2021; 11:698946. [PMID: 34307167 PMCID: PMC8298065 DOI: 10.3389/fonc.2021.698946] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 06/16/2021] [Indexed: 12/03/2022] Open
Abstract
Sex profoundly affects cancer incidence and susceptibility to therapy, with sex hormones highly contributing to this disparity. Various studies and omics data suggest a relationship between sex and the oncosuppressor p53 circuitry, including its regulators MDM2 and MDM4. Association of this network with genetic variation underlies sex-related altered cancer risk, age of onset, and cancer sensitivity to therapy. Moreover, sex-related factors, mainly estrogenic hormones, can affect the levels and/or function of the p53 network both in hormone-dependent and independent cancer. Despite this evidence, preclinical and clinical studies aimed to evaluate p53 targeted therapy rarely consider sex and related factors. This review summarizes the studies reporting the relationship between sex and the p53 circuitry, including its associated regulators, MDM2 and MDM4, with particular emphasis on estrogenic hormones. Moreover, we reviewed the evaluation of sex/hormone in preclinical studies and clinical trials employing p53-target therapies, and discuss how patients’ sex and hormonal status could impact these therapeutic approaches.
Collapse
Affiliation(s)
- Francesca Mancini
- Research Unit on Human Reproduction, International Scientific Institute Paul VI, Fondazione Policlinico A. Gemelli, IRCCS, Rome, Italy
| | - Ludovica Giorgini
- Institute of Biochemistry and Cell Biology, National Research Council of Italy, Monterotondo, Italy.,Catholic University of the Sacred Heart of Rome, Fondazione Policlinico A. Gemelli, IRCCS, Rome, Italy
| | - Emanuela Teveroni
- Research Unit on Human Reproduction, International Scientific Institute Paul VI, Fondazione Policlinico A. Gemelli, IRCCS, Rome, Italy
| | - Alfredo Pontecorvi
- Catholic University of the Sacred Heart of Rome, Fondazione Policlinico A. Gemelli, IRCCS, Rome, Italy
| | - Fabiola Moretti
- Institute of Biochemistry and Cell Biology, National Research Council of Italy, Monterotondo, Italy
| |
Collapse
|
|
13
|
LaPlante G, Zhang W. Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors. Cancers (Basel) 2021; 13:3079. [PMID: 34203106 PMCID: PMC8235664 DOI: 10.3390/cancers13123079] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/16/2021] [Accepted: 06/17/2021] [Indexed: 12/14/2022] Open
Abstract
The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation is implicated in numerous human diseases, including many types of cancer. Moreover, since cancer cells exhibit increased rates of protein turnover, their heightened dependence on the UPS makes it an attractive target for inhibition via targeted therapeutics. Indeed, the clinical application of proteasome inhibitors in treatment of multiple myeloma has been very successful, stimulating the development of small-molecule inhibitors targeting other UPS components. On the other hand, while the discovery of potent and selective chemical compounds can be both challenging and time consuming, the area of targeted protein degradation through utilization of the UPS machinery has seen promising developments in recent years. The repertoire of proteolysis-targeting chimeras (PROTACs), which employ E3 ligases for the degradation of cancer-related proteins via the proteasome, continues to grow. In this review, we will provide a thorough overview of small-molecule UPS inhibitors and highlight advancements in the development of targeted protein degradation strategies for cancer therapeutics.
Collapse
Affiliation(s)
- Gabriel LaPlante
- Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, 50 Stone Rd E, Guelph, ON N1G2W1, Canada;
| | - Wei Zhang
- Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, 50 Stone Rd E, Guelph, ON N1G2W1, Canada;
- CIFAR Azrieli Global Scholars Program, Canadian Institute for Advanced Research, MaRS Centre West Tower, 661 University Avenue, Toronto, ON M5G1M1, Canada
| |
Collapse
|
|
14
|
Design, synthesis, and biological evaluation of nitroisoxazole-containing spiro[pyrrolidin-oxindole] derivatives as novel glutathione peroxidase 4/mouse double minute 2 dual inhibitors that inhibit breast adenocarcinoma cell proliferation. Eur J Med Chem 2021; 217:113359. [PMID: 33725632 DOI: 10.1016/j.ejmech.2021.113359] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 03/02/2021] [Accepted: 03/02/2021] [Indexed: 02/05/2023]
Abstract
A series of highly active CF3-containing 3'-(nitroisoxazole)spiro[pyrrolidin-3,2'-oxindoles] were synthesized and found to be novel glutathione peroxidase 4 (GPX4)/mouse double minute 2 (MDM2) dual inhibitors. Bioactive spirooxindole and isoxazole skeletons were combined, and the resulting compounds exhibited strong activities against both targets. In particular, compound 3d displayed excellent activity in the suppression of MDM2-mediated degradation of p53, as well as levels of GPX4, in MCF-7 breast cancer cells. Moreover, 3d also exhibited inhibitory effects on MDM2 and GPX4 in MCF-7 xenograft model to trigger ferroptotic and apoptotic cell death in in vivo experiments, which was consistent with the results of in vitro experiments.
Collapse
|
|
15
|
Zanjirband M, Rahgozar S. Targeting p53-MDM2 Interaction Using Small Molecule Inhibitors and the Challenges Needed to be Addressed. Curr Drug Targets 2020; 20:1091-1111. [PMID: 30947669 DOI: 10.2174/1389450120666190402120701] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 03/25/2019] [Accepted: 03/26/2019] [Indexed: 12/16/2022]
Abstract
MDM2 protein is the core negative regulator of p53 that maintains the cellular levels of p53 at a low level in normal cells. Mutation of the TP53 gene accounts for 50% of all human cancers. In the remaining malignancies with wild-type TP53, p53 function is inhibited through other mechanisms. Recently, synthetic small molecule inhibitors have been developed which target a small hydrophobic pocket on MDM2 to which p53 normally binds. Given that MDM2-p53 antagonists have been undergoing clinical trials for different types of cancer, this review illustrates different aspects of these new cancer targeted therapeutic agents with the focus on the major advances in the field. It emphasizes on the p53 function, regulation of p53, targeting of the p53-MDM2 interaction for cancer therapy, and p53-dependent and -independent effects of inhibition of p53-MDM2 interaction. Then, representatives of small molecule MDM2-p53 binding antagonists are introduced with a focus on those entered into clinical trials. Furthermore, the review discusses the gene signatures in order to predict sensitivity to MDM2 antagonists, potential side effects and the reasons for the observed hematotoxicity, mechanisms of resistance to these drugs, their evaluation as monotherapy or in combination with conventional chemotherapy or with other targeted therapeutic agents. Finally, it highlights the certainly intriguing questions and challenges which would be addressed in future studies.
Collapse
Affiliation(s)
- Maryam Zanjirband
- Department of Cellular and Molecular Biology, Faculty of Science, University of Isfahan, Azadi Square, Isfahan, Iran
| | - Soheila Rahgozar
- Department of Cellular and Molecular Biology, Faculty of Science, University of Isfahan, Azadi Square, Isfahan, Iran
| |
Collapse
|
|
16
|
Konopleva M, Martinelli G, Daver N, Papayannidis C, Wei A, Higgins B, Ott M, Mascarenhas J, Andreeff M. MDM2 inhibition: an important step forward in cancer therapy. Leukemia 2020; 34:2858-2874. [PMID: 32651541 DOI: 10.1038/s41375-020-0949-z] [Citation(s) in RCA: 245] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 06/11/2020] [Accepted: 06/23/2020] [Indexed: 12/21/2022]
Abstract
Targeting the interaction between tumor suppressor p53 and the E3 ligase MDM2 represents an attractive treatment approach for cancers with wild-type or functional TP53. Indeed, several small molecules have been developed and evaluated in various malignancies. We provide an overview of MDM2 inhibitors under preclinical and clinical investigation, with a focus on molecules with ongoing clinical trials, as indicated by ClinicalTrials.gov . Because preclinical and clinical exploration of combination strategies is underway, data supporting these combinations are also described. We identified the following molecules for inclusion in this review: RG7112 (RO5045337), idasanutlin (RG7388), AMG-232 (KRT-232), APG-115, BI-907828, CGM097, siremadlin (HDM201), and milademetan (DS-3032b). Information about each MDM2 inhibitor was collected from major congress records and PubMed using the following search terms: each molecule name, "MDM2"and "HDM2." Only congress records were limited by date (January 1, 2012-March 6, 2020). Special attention was given to available data in hematologic malignancies; however, available safety data in any indication are reported. Overall, targeting MDM2 is a promising treatment strategy, as evidenced by the increasing number of MDM2 inhibitors entering the clinic. Additional clinical investigation is needed to further elucidate the role of MDM2 inhibitors in the treatment of human cancers.
Collapse
Affiliation(s)
- Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Giovanni Martinelli
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRST IRCCS, Meldola, FC, Italy
| | - Naval Daver
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Cristina Papayannidis
- Institute of Hematology "L. and A". Seràgnoli, University Hospital S. Orsola-Malpighi, Bologna, Italy
| | - Andrew Wei
- The Alfred Hospital, Monash University, Melbourne, VIC, Australia
| | | | - Marion Ott
- F. Hoffmann-La Roche, Basel, Switzerland
| | - John Mascarenhas
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Michael Andreeff
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
|
17
|
Rusiecki R, Witkowski J, Jaszczewska-Adamczak J. MDM2-p53 Interaction Inhibitors: The Current State-of-Art and Updated Patent Review (2010-Present). Recent Pat Anticancer Drug Discov 2020; 14:324-369. [DOI: 10.2174/1574892814666191022163540] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Revised: 10/09/2019] [Accepted: 10/15/2019] [Indexed: 01/10/2023]
Abstract
Background:
Mouse Double Minute 2 protein (MDM2) is a cellular regulator of p53 tumor
suppressor (p53). Inhibition of the interaction between MDM2 and p53 proteins is a promising anticancer
therapy.
Objective:
This updated patent review is an attempt to compile the research and achievements of the
various researchers working on small molecule MDM2 inhibitors from 2010 to date. We provide an
outlook into the future for therapy based on MDM2 inhibition by presenting an overview of the most
relevant patents which have recently appeared in the literature.
Methods:
Literature and recent patents focusing on the anticancer potential of MDM2-p53 interaction
inhibitors and its applications have been analyzed. We put the main emphasis on the most perspective
compounds which are or were examined in clinical trials.
Results:
Literature data indicated that MDM2 inhibitors are therapeutically effective in specific types
of cancer or non-cancer diseases. A great number of patents and research work around new MDM2-
p53 interaction inhibitors, possible combinations, new indications, clinical regimens in previous years
prove that this targeted therapy is in the scope of interest for many business and academic research
groups.
Conclusion:
Novel MDM2 inhibitors thanks to higher potency and better ADME properties have
shown effectiveness in preclinical and clinical development however the final improvement of therapeutic
potential for MDM2 inhibitors might depend on the useful combination therapy and exploring
new cancer and non-cancer indications.
Collapse
Affiliation(s)
- Rafał Rusiecki
- Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, Warsaw 00-664, Poland
| | - Jakub Witkowski
- Faculty of Chemistry, University of Warsaw, Pasteura 1, Warsaw 02-093, Poland
| | | |
Collapse
|
|
18
|
Barbosa K, Li S, Adams PD, Deshpande AJ. The role of TP53 in acute myeloid leukemia: Challenges and opportunities. Genes Chromosomes Cancer 2019; 58:875-888. [PMID: 31393631 PMCID: PMC12042961 DOI: 10.1002/gcc.22796] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 08/02/2019] [Accepted: 08/05/2019] [Indexed: 12/16/2022] Open
Abstract
The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancer. The central role of the TP53 protein in several fundamental processes such as cancer, aging, senescence, and DNA repair has ensured enormous attention. However, the role of TP53 in acute myeloid leukemia (AML) is enigmatic. Unlike many other human cancers, a vast majority of AMLs display no genomic TP53 alterations. There is now growing appreciation of the fact that the unaltered TP53 status of tumor cells can be exploited therapeutically. As most AMLs have an intact TP53 gene, its physiological tumor-suppressive roles could be harnessed. Therefore, the use of pharmacological activators of the TP53 pathway may provide clinical benefit in AML. Conversely, even though the frequency of TP53 mutations in AML is substantially lower than in other human cancers, TP53 mutations are associated with chemoresistance and high risk of relapse. In patients with TP53 mutations, these alterations may lead to novel, selective vulnerabilities, creating opportunities for therapeutic targeting of TP53 mutant AML. The mutational status of TP53 therefore poses challenges and opportunities in terms of advancing effective treatment strategies in AML. An increasing armamentarium of small-molecule activators of the TP53 pathway, and a growing understanding of molecular pathways triggered by mutant TP53 have accelerated efforts aimed at targeting TP53 function in AML. In combination with standard AML chemotherapy or emerging targeted therapies, pharmacological targeting of the TP53 pathway may provide therapeutic benefit in AML.
Collapse
Affiliation(s)
- Karina Barbosa
- Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Sha Li
- Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Peter D Adams
- Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Aniruddha J Deshpande
- Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| |
Collapse
|
|
19
|
Evaluating dose-limiting toxicities of MDM2 inhibitors in patients with solid organ and hematologic malignancies: A systematic review of the literature. Leuk Res 2019; 86:106222. [PMID: 31522038 DOI: 10.1016/j.leukres.2019.106222] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 08/30/2019] [Accepted: 09/05/2019] [Indexed: 01/08/2023]
Abstract
INTRODUCTION Mouse double minute 2 protein (MDM2), a negative regulator of the p53 tumour suppressor gene, is frequently amplified in malignancies. MDM2 antagonists have shown efficacy in treating malignancies with MDM2 overexpression and can overcome chemoresistance in acute myeloid leukemia. We systematically evaluated the safety profile of MDM2 inhibitors in the treatment of solid organ and hematologic malignancies. MATERIALS AND METHODS We searched Medline and EMBASE from January 1947 to November 2018 for prospective clinical studies, in English or French, investigating any MDM2 inhibitor in pediatric or adult cancers, and reporting dose and toxicity outcomes. Primary outcome was dose-limiting toxicity (DLT) and secondary outcome was death. RESULTS The search yielded 493 non-duplicate citations. Eighteen studies of 10 inhibitors met inclusion criteria (total N = 1005 patients). Two-thirds of included studies did not define DLTs and the reporting of toxicities was highly variable. The most commonly reported DLTs were cytopenias, gastrointestinal toxicity, metabolic disturbances, fatigue and cardiovascular toxicity; there was one death attributed to treatment toxicity. CONCLUSION MDM2 antagonists have been studied in a variety of malignancies with toxicities similar to other commonly used chemotherapy agents and may represent a safe adjuvant treatment for further study in in acute leukemia.
Collapse
|
|
20
|
Liao G, Yang D, Ma L, Li W, Hu L, Zeng L, Wu P, Duan L, Liu Z. The development of piperidinones as potent MDM2-P53 protein-protein interaction inhibitors for cancer therapy. Eur J Med Chem 2018; 159:1-9. [DOI: 10.1016/j.ejmech.2018.09.044] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 09/13/2018] [Accepted: 09/14/2018] [Indexed: 11/29/2022]
|
|
21
|
Macalino SJY, Basith S, Clavio NAB, Chang H, Kang S, Choi S. Evolution of In Silico Strategies for Protein-Protein Interaction Drug Discovery. Molecules 2018; 23:E1963. [PMID: 30082644 PMCID: PMC6222862 DOI: 10.3390/molecules23081963] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 08/03/2018] [Accepted: 08/04/2018] [Indexed: 12/14/2022] Open
Abstract
The advent of advanced molecular modeling software, big data analytics, and high-speed processing units has led to the exponential evolution of modern drug discovery and better insights into complex biological processes and disease networks. This has progressively steered current research interests to understanding protein-protein interaction (PPI) systems that are related to a number of relevant diseases, such as cancer, neurological illnesses, metabolic disorders, etc. However, targeting PPIs are challenging due to their "undruggable" binding interfaces. In this review, we focus on the current obstacles that impede PPI drug discovery, and how recent discoveries and advances in in silico approaches can alleviate these barriers to expedite the search for potential leads, as shown in several exemplary studies. We will also discuss about currently available information on PPI compounds and systems, along with their usefulness in molecular modeling. Finally, we conclude by presenting the limits of in silico application in drug discovery and offer a perspective in the field of computer-aided PPI drug discovery.
Collapse
Affiliation(s)
- Stephani Joy Y Macalino
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.
| | - Shaherin Basith
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.
| | - Nina Abigail B Clavio
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.
| | - Hyerim Chang
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.
| | - Soosung Kang
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.
| | - Sun Choi
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.
| |
Collapse
|
|
22
|
Arnhold V, Schmelz K, Proba J, Winkler A, Wünschel J, Toedling J, Deubzer HE, Künkele A, Eggert A, Schulte JH, Hundsdoerfer P. Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma. Oncotarget 2017; 9:2304-2319. [PMID: 29416773 PMCID: PMC5788641 DOI: 10.18632/oncotarget.23409] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 12/04/2017] [Indexed: 02/06/2023] Open
Abstract
Fewer than 50% of patients with high-risk neuroblastoma survive five years after diagnosis with current treatment protocols. Molecular targeted therapies are expected to improve survival. Although MDM2 has been validated as a promising target in preclinical models, no MDM2 inhibitors have yet entered clinical trials for neuroblastoma patients. Toxic side effects, poor bioavailability and low efficacy of the available MDM2 inhibitors that have entered phase I/II trials drive the development of novel MDM2 inhibitors with an improved risk-benefit profile. We investigated the effect of the novel MDM2 small molecular inhibitor, DS-3032b, on viability, proliferation, senescence, migration, cell cycle arrest and apoptosis in a panel of six neuroblastoma cell lines with different TP53 and MYCN genetic backgrounds, and assessed efficacy in a murine subcutaneous model for high-risk neuroblastoma. Re-analysis of existing expression data from 476 primary neuroblastomas showed that high-level MDM2 expression correlated with poor patient survival. DS-3032b treatment enhanced TP53 target gene expression and induced G1 cell cycle arrest, senescence and apoptosis. CRISPR-mediated MDM2 knockout in neuroblastoma cells mimicked DS-3032b treatment. TP53 signaling was selectively activated by DS-3032b in neuroblastoma cells with wildtype TP53, regardless of the presence of MYCN amplification, but was significantly reduced by TP53 mutations or expression of a dominant-negative TP53 mutant. Oral DS-3032b administration inhibited xenograft tumor growth and prolonged mouse survival. Our in vitro and in vivo data demonstrate that DS-3032b reactivates TP53 signaling even in the presence of MYCN amplification in neuroblastoma cells, to reduce proliferative capacity and cause cytotoxicity.
Collapse
Affiliation(s)
- Viktor Arnhold
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Hematology/Oncology/Stem Cell Transplantation, Berlin, Germany.,Berlin Institute of Health (BIH), Anna-Louisa-Karsch 2, Berlin, Germany
| | - Karin Schmelz
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Hematology/Oncology/Stem Cell Transplantation, Berlin, Germany
| | - Jutta Proba
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Hematology/Oncology/Stem Cell Transplantation, Berlin, Germany
| | - Annika Winkler
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Hematology/Oncology/Stem Cell Transplantation, Berlin, Germany
| | - Jasmin Wünschel
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Hematology/Oncology/Stem Cell Transplantation, Berlin, Germany
| | - Joern Toedling
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Hematology/Oncology/Stem Cell Transplantation, Berlin, Germany
| | - Hedwig E Deubzer
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Hematology/Oncology/Stem Cell Transplantation, Berlin, Germany.,Berlin Institute of Health (BIH), Anna-Louisa-Karsch 2, Berlin, Germany.,Neuroblastoma Research Group, Experimental and Clinical Research Center (ECRC), Berlin, Germany
| | - Annette Künkele
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Hematology/Oncology/Stem Cell Transplantation, Berlin, Germany.,Berlin Institute of Health (BIH), Anna-Louisa-Karsch 2, Berlin, Germany
| | - Angelika Eggert
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Hematology/Oncology/Stem Cell Transplantation, Berlin, Germany.,Berlin Institute of Health (BIH), Anna-Louisa-Karsch 2, Berlin, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Johannes H Schulte
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Hematology/Oncology/Stem Cell Transplantation, Berlin, Germany.,Berlin Institute of Health (BIH), Anna-Louisa-Karsch 2, Berlin, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Patrick Hundsdoerfer
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Hematology/Oncology/Stem Cell Transplantation, Berlin, Germany.,Berlin Institute of Health (BIH), Anna-Louisa-Karsch 2, Berlin, Germany
| |
Collapse
|
|
23
|
Abstract
OPINION STATEMENT Approximately 40-45% of younger and 10-20% of older adults with acute myeloid leukemia (AML) will be cured with current standard chemotherapy. The outlook is particularly gloomy for patients with relapsed and/or refractory disease (cure rates no higher than 10%). Allogeneic hematopoietic stem cell transplantation (HSCT), the only realistic hope of cure for these patients, is an option for only a minority. In recent years, much has been learned about the genomic and epigenomic landscapes of AML, and the clonal architecture of both de novo and secondary AML has begun to be unraveled. These advances have paved the way for rational drug development as new "drugable" targets have emerged. Although no new drug has been approved for AML in over four decades, with the exception of gemtuzumab ozogamycin, which was subsequently withdrawn, there is progress on the horizon with the possible regulatory approval soon of agents such as CPX-351 and midostaurin, the Food and Drug Administration "breakthrough" designation granted to venetoclax, and promising agents such as the IDH inhibitors AG-221 and AG-120, the smoothened inhibitor glasdegib and the histone deacetylase inhibitor pracinostat. In our practice, we treat most patients with relapsed/refractory AML on clinical trials, taking into consideration their prior treatment history and response to the same. We utilize targeted sequencing of genes frequently mutated in AML to identify "actionable" mutations, e.g., in FLT3 or IDH1/2, and incorporate small-molecule inhibitors of these oncogenic kinases into our therapeutic regimens whenever possible. In the absence of actionable mutations, we rationally combine conventional agents with other novel therapies such as monoclonal antibodies and other targeted drugs. For fit patients up to the age of 65, we often use high-dose cytarabine-containing backbone regimens. For older or unfit patients, we prefer hypomethylating agent-based therapy. Finally, all patients with relapsed/refractory AML are evaluated for allogeneic HSCT.
Collapse
|
|
24
|
Prokocimer M, Molchadsky A, Rotter V. Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy. Blood 2017; 130:699-712. [PMID: 28607134 PMCID: PMC5659817 DOI: 10.1182/blood-2017-02-763086] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 06/06/2017] [Indexed: 12/13/2022] Open
Abstract
The heterogeneous nature of acute myeloid leukemia (AML) and its poor prognosis necessitate therapeutic improvement. Current advances in AML research yield important insights regarding AML genetic, epigenetic, evolutional, and clinical diversity, all in which dysfunctional p53 plays a key role. As p53 is central to hematopoietic stem cell functions, its aberrations affect AML evolution, biology, and therapy response and usually predict poor prognosis. While in human solid tumors TP53 is mutated in more than half of cases, TP53 mutations occur in less than one tenth of de novo AML cases. Nevertheless, wild-type (wt) p53 dysfunction due to nonmutational p53 abnormalities appears to be rather frequent in various AML entities, bearing, presumably, a greater impact than is currently appreciated. Hereby, we advocate assessment of adult AML with respect to coexisting p53 alterations. Accordingly, we focus not only on the effects of mutant p53 oncogenic gain of function but also on the mechanisms underlying nonmutational wtp53 inactivation, which might be of therapeutic relevance. Patient-specific TP53 genotyping with functional evaluation of p53 protein may contribute significantly to the precise assessment of p53 status in AML, thus leading to the tailoring of a rationalized and precision p53-based therapy. The resolution of the mechanisms underlying p53 dysfunction will better address the p53-targeted therapies that are currently considered for AML. Additionally, a suggested novel algorithm for p53-based diagnostic workup in AML is presented, aiming at facilitating the p53-based therapeutic choices.
Collapse
MESH Headings
- Adult
- Animals
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- DNA Damage/drug effects
- Gene Expression Regulation, Leukemic/drug effects
- Genomic Instability/drug effects
- Hematopoiesis/drug effects
- Humans
- Karyopherins/genetics
- Karyopherins/metabolism
- Leukemia, Myeloid, Acute/diagnosis
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Molecular Targeted Therapy/methods
- Mutation/drug effects
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Nucleophosmin
- Protein Interaction Maps/drug effects
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, Cytoplasmic and Nuclear/metabolism
- Signal Transduction/drug effects
- Translocation, Genetic
- Tumor Suppressor Protein p53/analysis
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
- fms-Like Tyrosine Kinase 3/genetics
- fms-Like Tyrosine Kinase 3/metabolism
- Exportin 1 Protein
Collapse
Affiliation(s)
- Miron Prokocimer
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and
| | - Alina Molchadsky
- Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel
| | - Varda Rotter
- Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel
| |
Collapse
|
|
25
|
Tisato V, Voltan R, Gonelli A, Secchiero P, Zauli G. MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer. J Hematol Oncol 2017; 10:133. [PMID: 28673313 PMCID: PMC5496368 DOI: 10.1186/s13045-017-0500-5] [Citation(s) in RCA: 199] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 06/20/2017] [Indexed: 02/07/2023] Open
Abstract
The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed. The pharmacological targeting of these two P53-regulators in order to restore or increase P53 expression and activity represents therefore a strategy for cancer therapy. From the discovery of the Nutlins in 2004, several compounds have been developed and reported with the ability of targeting the P53-MDM2/X axis by inhibiting MDM2 and/or MDMX. From natural compounds up to small molecules and stapled peptides, these MDM2/X pharmacological inhibitors have been extensively studied, revealing different biological features and different rate of efficacy when tested in in vitro and in vivo experimental tumor models. The data/evidence coming from the preclinical experimentation have allowed the identification of the most promising molecules and the setting of clinical studies for their evaluation as monotherapy or in therapeutic combination with conventional chemotherapy or with innovative therapeutic protocols in different tumor settings. Preliminary results have been recently published reporting data about safety, tolerability, potential side effects, and efficacy of such therapeutic approaches. In this light, the aim of this review is to give an updated overview about the state of the art of the clinical evaluation of MDM2/X inhibitor compounds with a special attention to hematological malignancies and to the potential for the management of pediatric cancers.
Collapse
Affiliation(s)
- Veronica Tisato
- Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Via Fossato di Mortara 66, 44121, Ferrara, Italy.
| | - Rebecca Voltan
- Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Via Fossato di Mortara 66, 44121, Ferrara, Italy
| | - Arianna Gonelli
- Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Via Fossato di Mortara 66, 44121, Ferrara, Italy
| | - Paola Secchiero
- Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Via Fossato di Mortara 66, 44121, Ferrara, Italy
| | - Giorgio Zauli
- Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Via Fossato di Mortara 66, 44121, Ferrara, Italy
| |
Collapse
|