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1
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Kratochvilová L, Dinová A, Valková N, Dobrovolná M, Sánchez-Murcia PA, Brázda V. Chromatin Immunoprecipitation Reveals p53 Binding to G-Quadruplex DNA Sequences in Myeloid Leukemia Cell Lines. ACS BIO & MED CHEM AU 2025; 5:283-298. [PMID: 40255281 PMCID: PMC12006861 DOI: 10.1021/acsbiomedchemau.4c00124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/27/2025] [Accepted: 01/29/2025] [Indexed: 04/22/2025]
Abstract
Clarifying functions of the p53 protein is a crucial aspect of cancer research. We analyzed the binding sites of p53 wild-type (WT) protein and its oncologically significant mutants and evaluated their transactivation properties using a functional yeast assay. Unlike the binding sites as determined in myeloid leukemia cell lines by chromatin immunoprecipitation of p53-R175H, p53-Y220C, p53-M237I, p53-R248Q, and p53-R273H mutants, the target sites of p53-WT and p53-R282W were significantly associated with putative G-quadruplex sequences (PQSs). Guanine-quadruplex (G-quadruplex or G4) formation in these sequences was evaluated by using a set of biophysical methods. G4s can modulate gene expression induced by p53. At low p53 expression level, PQS upstream of the p53-response element (RE) leads to greater gene expression induced by p53-R282W compared to that for the RE without PQS. Meanwhile, p53-WT protein expression is decreased by the PQS presence. At a high p53 expression level, the presence of PQS leads to a decreased expression of the reporter regardless of the distance and localization of the G4 from the RE.
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Affiliation(s)
- Libuše Kratochvilová
- Institute
of Biophysics of the Czech Academy of Sciences, Královopolská 135, Brno 612 65, Czech Republic
- Department
of Food Chemistry and Biotechnology, Faculty of Chemistry, Brno University of Technology, Purkyňova 118, Brno 612 00, Czech Republic
| | - Alessandra Dinová
- Institute
of Biophysics of the Czech Academy of Sciences, Královopolská 135, Brno 612 65, Czech Republic
| | - Natália Valková
- Institute
of Biophysics of the Czech Academy of Sciences, Královopolská 135, Brno 612 65, Czech Republic
| | - Michaela Dobrovolná
- Institute
of Biophysics of the Czech Academy of Sciences, Královopolská 135, Brno 612 65, Czech Republic
- Department
of Food Chemistry and Biotechnology, Faculty of Chemistry, Brno University of Technology, Purkyňova 118, Brno 612 00, Czech Republic
| | - Pedro A. Sánchez-Murcia
- Laboratory
of Computer-Aided Molecular Design, Division of Medicinal Chemistry, Otto-Loewi Research Center, Neue Stiftingtalstr. 6/III, Graz A-8010, Austria
- BioTechMed-Graz, Mozartgasse 12/II, Graz A-8010, Austria
| | - Václav Brázda
- Institute
of Biophysics of the Czech Academy of Sciences, Královopolská 135, Brno 612 65, Czech Republic
- Department
of Food Chemistry and Biotechnology, Faculty of Chemistry, Brno University of Technology, Purkyňova 118, Brno 612 00, Czech Republic
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2
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Huang Y, Li W, Zhou Y, Bai J, Li N, Su Z, Cheng X. Strategies for p53 Activation and Targeted Inhibitors of the p53-Mdm2/MdmX Interaction. Cells 2025; 14:583. [PMID: 40277907 PMCID: PMC12025665 DOI: 10.3390/cells14080583] [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: 03/12/2025] [Revised: 04/06/2025] [Accepted: 04/10/2025] [Indexed: 04/26/2025] Open
Abstract
p53 is a tumor suppressor gene and is regarded as one of the most crucial genes in protecting humans against cancer. The protein Mdm2 and its homolog MdmX serve as negative regulators of p53. In nearly half of cancer cells, there is an overexpression of Mdm2 and MdmX, which inhibit p53 activity. Furthermore, Mdm2's E3 ubiquitin ligase activity promotes the ubiquitination and degradation of p53. Therefore, blocking the interaction between p53 and Mdm2/MdmX to prevent the degradation of wild-type p53 is an effective strategy for inhibiting tumor growth. This paper primarily discusses the regulatory relationship between p53, MdmX and Mdm2, and provides a review of the current status of p53-Mdm2/MdmX inhibitors. It aims to offer a theoretical foundation and research direction for the future discovery and design of targeted inhibitors against the p53-Mdm2/MdmX interaction.
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Affiliation(s)
- Ye Huang
- Institute of Modern Fermentation Engineering and Future Foods, School of Light Industry and Food Engineering, Guangxi University, No. 100, Daxuedong Road, Nanning 530004, China; (Y.H.); (W.L.); (Y.Z.); (J.B.); (N.L.)
| | - Wang Li
- Institute of Modern Fermentation Engineering and Future Foods, School of Light Industry and Food Engineering, Guangxi University, No. 100, Daxuedong Road, Nanning 530004, China; (Y.H.); (W.L.); (Y.Z.); (J.B.); (N.L.)
| | - Yuke Zhou
- Institute of Modern Fermentation Engineering and Future Foods, School of Light Industry and Food Engineering, Guangxi University, No. 100, Daxuedong Road, Nanning 530004, China; (Y.H.); (W.L.); (Y.Z.); (J.B.); (N.L.)
| | - Jinping Bai
- Institute of Modern Fermentation Engineering and Future Foods, School of Light Industry and Food Engineering, Guangxi University, No. 100, Daxuedong Road, Nanning 530004, China; (Y.H.); (W.L.); (Y.Z.); (J.B.); (N.L.)
| | - Ning Li
- Institute of Modern Fermentation Engineering and Future Foods, School of Light Industry and Food Engineering, Guangxi University, No. 100, Daxuedong Road, Nanning 530004, China; (Y.H.); (W.L.); (Y.Z.); (J.B.); (N.L.)
| | - Zhengding Su
- School of Pharmaceutical Sciences and Institute of Materia Medica, Xinjiang University, Urumqi 830017, China;
| | - Xiyao Cheng
- Institute of Modern Fermentation Engineering and Future Foods, School of Light Industry and Food Engineering, Guangxi University, No. 100, Daxuedong Road, Nanning 530004, China; (Y.H.); (W.L.); (Y.Z.); (J.B.); (N.L.)
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3
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Zhang XL, Yue HW, Liu YJ, Wang JY, Duan HT, Liu YH, Jiang LL, Hu HY. Designer polyQ fusion proteins sequester USP7/HDM2 for modulating P53 functionality. iScience 2025; 28:112025. [PMID: 40104064 PMCID: PMC11914518 DOI: 10.1016/j.isci.2025.112025] [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: 07/03/2024] [Revised: 11/05/2024] [Accepted: 02/11/2025] [Indexed: 03/20/2025] Open
Abstract
Overexpression of USP7 and HDM2 inactivates P53 signaling in tumor cells and facilitates their progression, but suppression of these targets by conventional strategies to reactivate P53 function remains a challenge. We applied polyQ sequences and target-interacting peptides to engineer polyQ fusion proteins that specifically sequester the targets, hence depleting their availabilities and modulating the P53 functionality. We have revealed that the designer fusion Atx793Q-N172-IRF (IRF sequence: SPGEGPSGTG) sequesters USP7 and/or HDM2 into aggregates and thereby increases the P53 level, but it depends on the IRF repeats fused, suggesting that depletion of the USP7 availability plays a dual role in controlling P53 stability. Direct sequestration of HDM2 by Atx793Q-N172-PMI (PMI: TSFAEYWNLLSP) remarkably reduces the protein level of soluble HDM2 and hence increases the P53 level, which consequently up-regulates expression of the downstream genes. The polyQ-fusion strategy is feasible to modulate the P53 stability and functionality, furnishing a therapeutic potential for cancers.
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Affiliation(s)
- Xiang-Le Zhang
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China
- University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Hong-Wei Yue
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China
- University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Ya-Jun Liu
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China
- University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Jian-Yang Wang
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China
- University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Heng-Tong Duan
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China
- University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Yin-Hu Liu
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China
- University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Lei-Lei Jiang
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China
| | - Hong-Yu Hu
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China
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4
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Barros HL, Espadinha M, Pinto SN, Ferreira RJF, Loureiro JB, Silva R, Saraiva L, Maçôas E, Santos MMM. Tryptophanol-derived oxazoloisoindolinone fluorescent probes for cellular localization studies of p53 activators. Bioorg Chem 2024; 153:107898. [PMID: 39454498 DOI: 10.1016/j.bioorg.2024.107898] [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: 07/09/2024] [Revised: 09/30/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024]
Abstract
The protein p53 is a transcription factor with several key roles in cells, including acting as a tumour suppressor. In most human cancers its tumour suppressor function is inactivated, either through inhibition by negative regulators or by mutation in the TP53 gene. Thus, there is a high interest in developing molecules able to activate p53 tumour suppressor activity. Tryptophanol-derived isoindolinones are known to act as wild-type and mutant p53 activators. Specifically, SLMP53-1 is a non-fluorescent wild-type and mutant p53 R280K reactivator, with potent in vivo anti-tumour activity in HCT116 and MDA-MB-231 mice xenograft models. With the aim of studying tryptophanol-derived isoindolinones intracellular localization by fluorescence microscopy, three SLMP53-1 based fluorescent probes were prepared. Here we report the design, synthesis, photophysical characterization, antiproliferative activity and cell localization studies of these fluorescent probes. The previously described structure-activity relationships of the SLMP53-1 scaffold set the basis for the design the fluorescent probes. The probes were prepared by connecting a small fluorophore (dansyl or 7-nitrobenzofurazan) to the indole nitrogen of the tryptophanol-derived oxazoloisoindolinone SLMP53-1 through two different linkers. The antiproliferative activity and cell localization studies of the three fluorescent probes were performed in HCT116 cells. The three probes showed enhanced internalization when compared with their fluorophore-linker intermediates, good photo-stability and high affinity for the endoplasmic reticulum, indicating the potential involvement of endoplasmic reticulum in the mechanism of action of tryptophanol-derived oxazoloisoindolinones.
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Affiliation(s)
- Hélio L Barros
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
| | - Margarida Espadinha
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
| | - Sandra N Pinto
- Institute for Bioengineering and Biosciences (IBB), Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal; Associate Laboratory - Institute for Health and Bioeconomy (i4HB), Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Ricardo J F Ferreira
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
| | - Joana B Loureiro
- LAQV/REQUIMTE, Laboratόrio de Microbiologia, Departamento de Ciências Biolόgicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal
| | - Rita Silva
- LAQV/REQUIMTE, Laboratόrio de Microbiologia, Departamento de Ciências Biolόgicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal
| | - Lucília Saraiva
- LAQV/REQUIMTE, Laboratόrio de Microbiologia, Departamento de Ciências Biolόgicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal
| | - Ermelinda Maçôas
- Centro de Química Estrutural (CQE) and Institute of Molecular Sciences (IMS), Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal.
| | - Maria M M Santos
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
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5
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Alanzi AR. Exploring Microbial Dark Matter for the Discovery of Novel Natural Products: Characteristics, Abundance Challenges and Methods. J Microbiol Biotechnol 2024; 35:e2407064. [PMID: 39639495 PMCID: PMC11813339 DOI: 10.4014/jmb.2407.07064] [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: 08/14/2024] [Revised: 10/22/2024] [Accepted: 10/30/2024] [Indexed: 12/07/2024]
Abstract
The objective of this review is to investigate microbial dark matter (MDM) with a focus on its potential for discovering novel natural products (NPs). This first part will examine the characteristics and abundance of these previously unexplored microbial communities, as well as the challenges faced in identifying and harnessing their unique biochemical properties and novel methods in this field. MDMs are thought to hold great potential for the discovery of novel NPs, which could have significant applications in medicine, agriculture, and industry. In recent years, there has been a growing interest in exploring MDM to unlock its potential. In fact, developments in genome-sequencing technologies and sophisticated phylogenetic procedures and metagenomic techniques have contributed to drastically make important changes in our sights on the diversity of microbial life, including the very outline of the tree of life. This has led to the development of novel technologies and methodologies for studying these elusive microorganisms, such as single-cell genomics, metagenomics, and culturomics. These approaches enable researchers to isolate and analyze individual microbial cells, as well as entire communities, providing insights into their genetic and metabolic potential. By delving into the MDM, scientists hope to uncover new compounds and biotechnological advancements that could have far-reaching impacts on various fields.
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Affiliation(s)
- Abdullah R Alanzi
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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6
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Xu L, Fan X, He Y, Xia X, Zhang J. Design, Synthesis, and Biological Evaluation of Lysine-Stapled Peptide Inhibitors of p53-MDM2/MDMX Interactions with Potent Antitumor Activity In Vivo. J Med Chem 2024; 67:17893-17904. [PMID: 39300610 DOI: 10.1021/acs.jmedchem.4c01939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2024]
Abstract
We introduce novel lysine-stapled peptide inhibitors targeting p53-MDM2/MDMX interactions. Leveraging the model peptides pDI (LTFEHYWAQLTS) and PMI-M3 (LTFLEYWAQLMQ) as starting points, a series of lysine-stapled analogues were designed and synthesized. Through in vitro cell assay screening, two lead compounds, SPDI-48-T1 and SPMI-48-T3, were identified for their excellent antiproliferation activity. Fluorescence polarization assays revealed that both compounds exhibited strong binding affinities against MDM2 and MDMX, ascertained by Kd values within the low micromolar spectrum. Further characterization of SPDI-48-T1 and SPMI-48-T3 demonstrated that SPDI-48-T1 possessed superior cell permeability and serum stability. Notably, SPDI-48-T1 displayed a dose-dependent suppression of tumor growth in an HCT116 xenograft mouse model. Our findings indicate that SPDI-48-T1 holds promise as a lead compound for further development as an anticancer agent by modulating p53-MDM2/MDMX interactions. Additionally, this study also proved that the lysine stapling strategy may serve as a robust approach for generating peptide ligands targeting other protein-protein interactions.
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Affiliation(s)
- Lei Xu
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, People's Republic of China
| | - Xin Fan
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, People's Republic of China
| | - Yi He
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, People's Republic of China
| | - Xuefeng Xia
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, People's Republic of China
| | - Jinqiang Zhang
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, People's Republic of China
- Chongqing University Industrial Technology Research Institute, Chongqing 401329, People's Republic of China
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7
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Yin Q, Hu Y, Dong Z, Lu J, Wang H. Cellular, Structural Basis, and Recent Progress for Targeting Murine Double Minute X (MDMX) in Tumors. J Med Chem 2024; 67:14723-14741. [PMID: 39185935 DOI: 10.1021/acs.jmedchem.4c00913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Murine double minute X (MDMX) is an oncoprotein that mainly has a negative regulatory effect on the tumor suppressor p53 to induce tumorigenesis. As MDMX is highly expressed in various types of tumor cells, targeting and inhibiting MDMX are becoming a promising strategy for treating cancers. However, the high degree of structural homology between MDMX and its homologous protein murine double minute 2 (MDM2) is a great challenge for the development of MDMX-targeted therapies. This review introduces the structure, distribution, and regulation of the MDMX, summarizes the structural features and structure-activity relationships (SARs) of MDMX ligands, and focuses on the differences between MDMX and MDM2 in these aspects. Our purpose of this work is to propose potential strategies to achieve the specific targeting of MDMX.
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Affiliation(s)
- Qikun Yin
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
| | - Yuemiao Hu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
| | - Zhiwen Dong
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
| | - Jing Lu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
| | - Hongbo Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
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Liu F, Chen J, Li K, Li H, Zhu Y, Zhai Y, Lu B, Fan Y, Liu Z, Chen X, Jia X, Dong Z, Liu K. Ubiquitination and deubiquitination in cancer: from mechanisms to novel therapeutic approaches. Mol Cancer 2024; 23:148. [PMID: 39048965 PMCID: PMC11270804 DOI: 10.1186/s12943-024-02046-3] [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: 04/17/2024] [Accepted: 06/15/2024] [Indexed: 07/27/2024] Open
Abstract
Ubiquitination, a pivotal posttranslational modification of proteins, plays a fundamental role in regulating protein stability. The dysregulation of ubiquitinating and deubiquitinating enzymes is a common feature in various cancers, underscoring the imperative to investigate ubiquitin ligases and deubiquitinases (DUBs) for insights into oncogenic processes and the development of therapeutic interventions. In this review, we discuss the contributions of the ubiquitin-proteasome system (UPS) in all hallmarks of cancer and progress in drug discovery. We delve into the multiple functions of the UPS in oncology, including its regulation of multiple cancer-associated pathways, its role in metabolic reprogramming, its engagement with tumor immune responses, its function in phenotypic plasticity and polymorphic microbiomes, and other essential cellular functions. Furthermore, we provide a comprehensive overview of novel anticancer strategies that leverage the UPS, including the development and application of proteolysis targeting chimeras (PROTACs) and molecular glues.
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Affiliation(s)
- Fangfang Liu
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450000, China
| | - Jingyu Chen
- Department of Pediatric Medicine, School of Third Clinical Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Kai Li
- Department of Clinical Medicine, School of First Clinical Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Haochen Li
- Department of Clinical Medicine, School of First Clinical Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Yiyi Zhu
- Department of Clinical Medicine, School of First Clinical Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Yubo Zhai
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Bingbing Lu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Yanle Fan
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450000, China
| | - Ziyue Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Xiaojie Chen
- School of Basic Medicine, Henan University of Science and Technology, Luoyang, China
| | - Xuechao Jia
- Henan International Joint Laboratory of TCM Syndrome and Prescription in Signaling, Traditional Chinese Medicine (Zhong Jing) School, Henan University of Chinese Medicine, Zhengzhou, Henan, China.
| | - Zigang Dong
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450000, China.
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
| | - Kangdong Liu
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China.
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
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9
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Li Y, Wan L, Li H, Tang X, Xu S, Sun G, Huang W, Tang M. Small molecule NMD and MDM2 inhibitors synergistically trigger apoptosis in HeLa cells. Mol Cells 2024; 47:100079. [PMID: 38871298 PMCID: PMC11250858 DOI: 10.1016/j.mocell.2024.100079] [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: 02/06/2024] [Revised: 06/06/2024] [Accepted: 06/06/2024] [Indexed: 06/15/2024] Open
Abstract
The nonsense-mediated mRNA decay (NMD) pathway and the p53 pathway, linked to tumorgenesis, are also promising targets for cancer treatment. NMD plays an important role in RNA quality control, while the p53 pathway is involved in cancer suppression. However, their individual and combined effects on cervical cancer are poorly understood. In this study, we evaluated the impacts of NMD inhibitor, Mouse double minute 2 homolog (MDM2) inhibitor, and their combination on cell apoptosis, cell cycle, and p53 target genes in human papillomavirus-18-positive HeLa cells. Our findings revealed that XR-2 failed to activate p53 or induce apoptosis in HeLa cells, whereas SMG1 (serine/threonine-protein kinase 1) inhibitor repressed cell proliferation at high concentrations. Notably, the combination of these 2 agents significantly inhibited cell proliferation, arrested the cell cycle, and triggered cell apoptosis. Mechanistically, MDM2 inhibitor and NMD inhibitor likely exert a synergistically through the truncated E6 protein. These results underscore the potential of employing a combination of MDM2 inhibitor and NMD inhibitor as a promising candidate for the clinical treatment of human papillomavirus-infected tumors.
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Affiliation(s)
- Ying Li
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, PR China; Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Li Wan
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, PR China
| | - Hexin Li
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, PR China
| | - Xiaokun Tang
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, PR China
| | - Siyuan Xu
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, PR China
| | - Gaoyuan Sun
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, PR China
| | - Wei Huang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, PR China
| | - Min Tang
- Department of Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, PR China.
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10
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Regunath K, Fomin V, Liu Z, Wang P, Hoque M, Tian B, Rabadan R, Prives C. Systematic Characterization of p53-Regulated Long Noncoding RNAs across Human Cancers Reveals Remarkable Heterogeneity among Different Tumor Types. Mol Cancer Res 2024; 22:555-571. [PMID: 38393317 DOI: 10.1158/1541-7786.mcr-23-0295] [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: 05/01/2023] [Revised: 12/04/2023] [Accepted: 02/21/2024] [Indexed: 02/25/2024]
Abstract
The p53 tumor suppressor protein, a sequence-specific DNA binding transcription factor, regulates the expression of a large number of genes, in response to various forms of cellular stress. Although the protein coding target genes of p53 have been well studied, less is known about its role in regulating long noncoding genes and their functional relevance to cancer. Here we report the genome-wide identification of a large set (>1,000) of long noncoding RNAs (lncRNA), which are putative p53 targets in a colon cancer cell line and in human patient datasets from five different common types of cancer. These lncRNAs have not been annotated by other studies of normal unstressed systems. In the colon cancer cell line, a high proportion of these lncRNAs are uniquely induced by different chemotherapeutic agents that activate p53, whereas others are induced by more than one agent tested. Further, subsets of these lncRNAs independently predict overall and disease-free survival of patients across the five different common cancer types. Interestingly, both genetic alterations and patient survival associated with different lncRNAs are unique to each cancer tested, indicating extraordinary tissue-specific variability in the p53 noncoding response. The newly identified noncoding p53 target genes have allowed us to construct a classifier for tumor diagnosis and prognosis. IMPLICATIONS Our results not only identify myriad p53-regulated long noncoding (lncRNA), they also reveal marked drug-induced, as well as tissue- and tumor-specific heterogeneity in these putative p53 targets and our findings have enabled the construction of robust classifiers for diagnosis and prognosis.
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Affiliation(s)
- Kausik Regunath
- Department of Biological Sciences, Columbia University, New York, New York
| | - Vitalay Fomin
- Department of Biological Sciences, Columbia University, New York, New York
| | - Zhaoqi Liu
- Program for Mathematical Genomics, Departments of Systems Biology and Biomedical Informatics, Columbia University College of Physicians & Surgeons, New York, New York
| | - Pingzhang Wang
- Program for Mathematical Genomics, Departments of Systems Biology and Biomedical Informatics, Columbia University College of Physicians & Surgeons, New York, New York
| | - Mainul Hoque
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, New Jersey
| | - Bin Tian
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, New Jersey
| | - Raul Rabadan
- Program for Mathematical Genomics, Departments of Systems Biology and Biomedical Informatics, Columbia University College of Physicians & Surgeons, New York, New York
| | - Carol Prives
- Department of Biological Sciences, Columbia University, New York, New York
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11
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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: 0] [Impact Index Per Article: 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.
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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.)
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12
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Lin Z, Liu C, Yan Z, Cheng J, Wang X, Zhou F, Lyu X, Zhang S, Zhang D, Meng X, Zhao Y. Synthesis and biological evaluation of 4-imidazolidinone-containing compounds as potent inhibitors of the MDM2/p53 interaction. Eur J Med Chem 2024; 270:116366. [PMID: 38581730 DOI: 10.1016/j.ejmech.2024.116366] [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: 02/05/2024] [Revised: 03/19/2024] [Accepted: 03/27/2024] [Indexed: 04/08/2024]
Abstract
Inhibition of MDM2/p53 interaction with small-molecule inhibitors stabilizes p53 from MDM2 mediated degradation, which is a promising strategy for the treatment of cancer. In this report, a novel series of 4-imidazolidinone-containing compounds have been synthesized and tested in MDM2/p53 and MDM4/p53 FP binding assays. Upon SAR studies, compounds 2 (TB114) and 22 were identified as the most potent inhibitors of MDM2/p53 but not MDM4/p53 interactions. Both 2 and 22 exhibited strong antiproliferative activities in HCT-116 and MOLM-13 cell lines harboring wild type p53. Mechanistic studies show that 2 and 22 dose-dependently activated p53 and its target genes and induced apoptosis in cells based on the Western blot, qPCR, and flow cytometry assays. In addition, the antiproliferative activities of 2 and 22 were dependent on wild type p53, while they were not toxic to HEK-293 kidney cells. Furthermore, the on-target activities of 2 were general and applicable to other cancer cell lines with wild type p53. These attributes make 2 a good candidate for future optimization to discover a potential treatment of wild-type p53 cancer.
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Affiliation(s)
- Zhitong Lin
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road Shanghai, 201203, China
| | - Chen Liu
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road Shanghai, 201203, China
| | - Ziqin Yan
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road Shanghai, 201203, China
| | - Jing Cheng
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China
| | - Xiancheng Wang
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China
| | - Feilong Zhou
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road Shanghai, 201203, China
| | - Xilin Lyu
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road Shanghai, 201203, China
| | - Shiyan Zhang
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China
| | - Daizhou Zhang
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan, 250101, China
| | - Xiangjing Meng
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan, 250101, China.
| | - Yujun Zhao
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China; Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan, 250101, China.
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13
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Ren Y, Wu R, Li C, Liu L, Li L, Weng S, Xu H, Xing Z, Zhang Y, Wang L, Liu Z, Han X. Single-cell RNA sequencing integrated with bulk RNA sequencing analysis identifies a tumor immune microenvironment-related lncRNA signature in lung adenocarcinoma. BMC Biol 2024; 22:69. [PMID: 38519942 PMCID: PMC10960411 DOI: 10.1186/s12915-024-01866-5] [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: 06/27/2023] [Accepted: 03/13/2024] [Indexed: 03/25/2024] Open
Abstract
BACKGROUND Recently, long non-coding RNAs (lncRNAs) have been demonstrated as essential roles in tumor immune microenvironments (TIME). Nevertheless, researches on the clinical significance of TIME-related lncRNAs are limited in lung adenocarcinoma (LUAD). METHODS Single-cell RNA sequencing and bulk RNA sequencing data are integrated to identify TIME-related lncRNAs. A total of 1368 LUAD patients are enrolled from 6 independent datasets. An integrative machine learning framework is introduced to develop a TIME-related lncRNA signature (TRLS). RESULTS This study identified TIME-related lncRNAs from integrated analysis of single‑cell and bulk RNA sequencing data. According to these lncRNAs, a TIME-related lncRNA signature was developed and validated from an integrative procedure in six independent cohorts. TRLS exhibited a robust and reliable performance in predicting overall survival. Superior prediction performance barged TRLS to the forefront from comparison with general clinical features, molecular characters, and published signatures. Moreover, patients with low TRLS displayed abundant immune cell infiltration and active lipid metabolism, while patients with high TRLS harbored significant genomic alterations, high PD-L1 expression, and elevated DNA damage repair (DDR) relevance. Notably, subclass mapping analysis of nine immunotherapeutic cohorts demonstrated that patients with high TRLS were more sensitive to immunotherapy. CONCLUSIONS This study developed a promising tool based on TIME-related lncRNAs, which might contribute to tailored treatment and prognosis management of LUAD patients.
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Affiliation(s)
- Yuqing Ren
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Ruhao Wu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Chunwei Li
- Internet Medical and System Applications of National Engineering Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Long Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shanxi, China
| | - Lifeng Li
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Siyuan Weng
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Hui Xu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Zhe Xing
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Yuyuan Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Libo Wang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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14
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Zhong Y, Zeng W, Chen Y, Zhu X. The effect of lipid metabolism on cuproptosis-inducing cancer therapy. Biomed Pharmacother 2024; 172:116247. [PMID: 38330710 DOI: 10.1016/j.biopha.2024.116247] [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: 12/09/2023] [Revised: 02/01/2024] [Accepted: 02/01/2024] [Indexed: 02/10/2024] Open
Abstract
Cuproptosis provides a new therapeutic strategy for cancer treatment and is thought to have broad clinical application prospects. Nevertheless, some oncological clinical trials have yet to demonstrate favorable outcomes, highlighting the need for further research into the molecular mechanisms underlying cuproptosis in tumors. Cuproptosis primarily hinges on the intracellular accumulation of copper, with lipid metabolism exerting a profound influence on its course. The interaction between copper metabolism and lipid metabolism is closely related to cuproptosis. Copper imbalance can affect mitochondrial respiration and lipid metabolism changes, while lipid accumulation can promote copper uptake and absorption, and inhibit cuproptosis induced by copper. Anomalies in lipid metabolism can disrupt copper homeostasis within cells, potentially triggering cuproptosis. The interaction between cuproptosis and lipid metabolism regulates the occurrence, development, metastasis, chemotherapy drug resistance, and tumor immunity of cancer. Cuproptosis is a promising new target for cancer treatment. However, the influence of lipid metabolism and other factors should be taken into consideration. This review provides a brief overview of the characteristics of the interaction between cuproptosis and lipid metabolism in cancer and analyses potential strategies of applying cuproptosis for cancer treatment.
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Affiliation(s)
- Yue Zhong
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Wei Zeng
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Yongbo Chen
- Rehabilitation College of Gannan Medical University, Ganzhou 341000, China
| | - Xiuzhi Zhu
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China.
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15
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Ward JA, Romartinez-Alonso B, Kay DF, Bellamy-Carter J, Thurairajah B, Basran J, Kwon H, Leney AC, Macip S, Roversi P, Muskett FW, Doveston RG. Characterizing the protein-protein interaction between MDM2 and 14-3-3σ; proof of concept for small molecule stabilization. J Biol Chem 2024; 300:105651. [PMID: 38237679 PMCID: PMC10864208 DOI: 10.1016/j.jbc.2024.105651] [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: 10/11/2023] [Revised: 12/01/2023] [Accepted: 01/01/2024] [Indexed: 02/10/2024] Open
Abstract
Mouse Double Minute 2 (MDM2) is a key negative regulator of the tumor suppressor protein p53. MDM2 overexpression occurs in many types of cancer and results in the suppression of WT p53. The 14-3-3 family of adaptor proteins are known to bind MDM2 and the 14-3-3σ isoform controls MDM2 cellular localization and stability to inhibit its activity. Therefore, small molecule stabilization of the 14-3-3σ/MDM2 protein-protein interaction (PPI) is a potential therapeutic strategy for the treatment of cancer. Here, we provide a detailed biophysical and structural characterization of the phosphorylation-dependent interaction between 14-3-3σ and peptides that mimic the 14-3-3 binding motifs within MDM2. The data show that di-phosphorylation of MDM2 at S166 and S186 is essential for high affinity 14-3-3 binding and that the binary complex formed involves one MDM2 di-phosphorylated peptide bound to a dimer of 14-3-3σ. However, the two phosphorylation sites do not simultaneously interact so as to bridge the 14-3-3 dimer in a 'multivalent' fashion. Instead, the two phosphorylated MDM2 motifs 'rock' between the two binding grooves of the dimer, which is unusual in the context of 14-3-3 proteins. In addition, we show that the 14-3-3σ-MDM2 interaction is amenable to small molecule stabilization. The natural product fusicoccin A forms a ternary complex with a 14-3-3σ dimer and an MDM2 di-phosphorylated peptide resulting in the stabilization of the 14-3-3σ/MDM2 PPI. This work serves as a proof-of-concept of the drugability of the 14-3-3/MDM2 PPI and paves the way toward the development of more selective and efficacious small molecule stabilizers.
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Affiliation(s)
- Jake A Ward
- Leicester Institute for Structural and Chemical Biology, University of Leicester, Leicester, UK; Mechanisms of Cancer and Aging Laboratory, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK
| | - Beatriz Romartinez-Alonso
- Leicester Institute for Structural and Chemical Biology, University of Leicester, Leicester, UK; Department of Molecular and Cell Biology, University of Leicester, Leicester, UK
| | - Danielle F Kay
- School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK
| | | | - Bethany Thurairajah
- Leicester Institute for Structural and Chemical Biology, University of Leicester, Leicester, UK; School of Chemistry, University of Leicester, Leicester, UK
| | - Jaswir Basran
- Department of Molecular and Cell Biology, University of Leicester, Leicester, UK
| | - Hanna Kwon
- Leicester Institute for Structural and Chemical Biology, University of Leicester, Leicester, UK; Department of Molecular and Cell Biology, University of Leicester, Leicester, UK
| | - Aneika C Leney
- School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Salvador Macip
- Mechanisms of Cancer and Aging Laboratory, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK; FoodLab, Faculty of Health Sciences, Universitat Oberta de Catalunya, Barcelona, Spain; Josep Carreras Leukaemia Research Institute, Ctra de Can Ruti, Camí de les Escoles, s/n, Badalona, Barcelona, Spain
| | - Pietro Roversi
- Leicester Institute for Structural and Chemical Biology, University of Leicester, Leicester, UK; Institute of Agricultural Biology and Biotechnology, C.N.R., Unit of Milan, Milano, Italy
| | - Frederick W Muskett
- Leicester Institute for Structural and Chemical Biology, University of Leicester, Leicester, UK; Department of Molecular and Cell Biology, University of Leicester, Leicester, UK
| | - Richard G Doveston
- Leicester Institute for Structural and Chemical Biology, University of Leicester, Leicester, UK; School of Chemistry, University of Leicester, Leicester, UK.
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16
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Mehri A, Mahnam K, Sirous H, Aghaei M, Rafiei L, Rostami M. Dihydropyrimidine derivatives as MDM2 inhibitors. Chem Biol Drug Des 2024; 103:e14399. [PMID: 38011915 DOI: 10.1111/cbdd.14399] [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: 06/14/2023] [Revised: 08/22/2023] [Accepted: 11/07/2023] [Indexed: 11/29/2023]
Abstract
One of the chief pathways to regulate p53 levels is MDM2 protein, which negatively controls p53 by direct inhibition. Many cancers overproduce MDM2 protein to interrupt p53 functions. Therefore, impeding MDM2's binding to p53 can reactivate p53 in tumor cells may suggest an effective approach for tumor therapy. Here, some Monastrol derivatives were designed in silico as MDM2 inhibitors, and their initial cytotoxicity was evaluated in vitro on MFC-7 and MDA-MB-231 cells. A small library of Monastrol derivatives was created, and virtual screening (VS) was performed on them. The first-ranked compound, which was extracted from VS, and the other six compounds 5a-5f were selected to carry out the single-docking and docking with explicit waters. The compound with the best average results was then subjected to molecular dynamic (MD) simulation. Compounds 5a-5f were chemically synthesized and evaluated in vitro for their initial cytotoxicity on MFC-7 and MDA-MB-231 cells by MTT assay. The best compound was compound 5d with ΔGave = -10.35 kcal/mol. MD simulation revealed a median potency in comparison with Nutlin-3a. The MTT assay confirmed the docking and MD experiments. 5d has an IC50 of 60.09 μM on MCF-7 cells. We attempted to use Monastrol scaffold as a potent inhibitor of MDM2 rather than an Eg5 inhibitor using in silico modification. The results obtained from the in silico and in vitro evaluations were noteworthy and warranted much more effort in the future.
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Affiliation(s)
- Ali Mehri
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Science, Isfahan University of Medical Science, Isfahan, Iran
| | - Karim Mahnam
- Biology Department, Faculty of Sciences, Shahrekord University, Shahrekord, Iran
| | - Hajar Sirous
- Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Science, Isfahan, Iran
| | - Mahmoud Aghaei
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Science, Isfahan, Iran
| | - Leila Rafiei
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Science, Isfahan University of Medical Science, Isfahan, Iran
| | - Mahboubeh Rostami
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Science, Isfahan University of Medical Science, Isfahan, Iran
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17
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Cheng J, Yan Z, Jiang K, Liu C, Xu D, Lyu X, Hu X, Zhang S, Zhou Y, Li J, Zhao Y. Discovery of JN122, a Spiroindoline-Containing Molecule that Inhibits MDM2/p53 Protein-Protein Interaction and Exerts Robust In Vivo Antitumor Efficacy. J Med Chem 2023; 66:16991-17025. [PMID: 38062557 DOI: 10.1021/acs.jmedchem.3c01815] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2023]
Abstract
MDM2 and MDM4 cooperatively and negatively regulate p53, while this pathway is often hijacked by cancer cells in favor of their survival. Blocking MDM2/p53 interaction with small-molecule inhibitors liberates p53 from MDM2 mediated degradation, which is an attractive strategy for drug discovery. We reported herein structure-based discovery of highly potent spiroindoline-containing MDM2 inhibitor (-)60 (JN122), which also exhibited moderate activities against MDM4/p53 interactions. In a panel of cancer cell lines harboring wild type p53, (-)60 efficiently promoted activation of p53 and its target genes, inhibited cell cycle progression, and induced cell apoptosis. Interestingly, (-)60 also promoted degradation of MDM4. More importantly, (-)60 exhibited good PK properties and exerted robust antitumor efficacies in a systemic mouse xenograft model of MOLM-13. Taken together, our study showcases a class of potent MDM2 inhibitors featuring a novel spiro-indoline scaffold, which is promising for future development targeting cancer cells with wild-type p53.
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Affiliation(s)
- Jing Cheng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, P. R. China
- University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, P. R. China
| | - Ziqin Yan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, P. R. China
| | - Kailong Jiang
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, P. R. China
| | - Chen Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, P. R. China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
| | - Dehua Xu
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, P. R. China
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124000, P. R. China
| | - Xilin Lyu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, P. R. China
| | - Xiaobei Hu
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, P. R. China
| | - Shiyan Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, P. R. China
- University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, P. R. China
| | - Yubo Zhou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, P. R. China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, P. R. China
| | - Jia Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, P. R. China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, P. R. China
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124000, P. R. China
| | - Yujun Zhao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, P. R. China
- University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, P. R. China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, P. R. China
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P. R. China
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18
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AbdulHussein AH, Al-Taee MM, Radih ZA, Aljuboory DS, Mohammed ZQ, Hashesh TS, Riadi Y, Hadrawi SK, Najafi M. Mechanisms of cancer cell death induction by triptolide. Biofactors 2023; 49:718-735. [PMID: 36876465 DOI: 10.1002/biof.1944] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 02/21/2023] [Indexed: 03/07/2023]
Abstract
Drug resistance is a hot topic issue in cancer research and therapy. Although cancer therapy including radiotherapy and anti-cancer drugs can kill malignant cells within the tumor, cancer cells can develop a wide range of mechanisms to resist the toxic effects of anti-cancer agents. Cancer cells may provide some mechanisms to resist oxidative stress and escape from apoptosis and attack by the immune system. Furthermore, cancer cells may resist senescence, pyroptosis, ferroptosis, necroptosis, and autophagic cell death by modulating several critical genes. The development of these mechanisms leads to resistance to anti-cancer drugs and also radiotherapy. Resistance to therapy can increase mortality and reduce survival following cancer therapy. Thus, overcoming mechanisms of resistance to cell death in malignant cells can facilitate tumor elimination and increase the efficiency of anti-cancer therapy. Natural-derived molecules are intriguing agents that may be suggested to be used as an adjuvant in combination with other anticancer drugs or radiotherapy to sensitize cancer cells to therapy with at least side effects. This paper aims to review the potential of triptolide for inducing various types of cell death in cancer cells. We review the induction or resistance to different cell death mechanisms such as apoptosis, autophagic cell death, senescence, pyroptosis, ferroptosis, and necrosis following the administration of triptolide. We also review the safety and future perspectives for triptolide and its derivatives in experimental and human studies. The anticancer potential of triptolide and its derivatives may make them effective adjuvants for enhancing tumor suppression in combination with anticancer therapy.
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Affiliation(s)
| | | | | | | | | | | | - Yassine Riadi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Salema K Hadrawi
- Refrigeration and Air-Conditioning Technical Engineering Department, College of Technical Engineering, The Islamic University, Najaf, Iraq
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
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19
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Wang C, Zhu M, Long X, Wang Q, Wang Z, Ouyang G. Design, Synthesis and Antitumor Activity of 1 H-indazole-3-amine Derivatives. Int J Mol Sci 2023; 24:ijms24108686. [PMID: 37240028 DOI: 10.3390/ijms24108686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/08/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
A series of indazole derivatives were designed and synthesized by molecular hybridization strategy, and these compounds were evaluated the inhibitory activities against human cancer cell lines of lung (A549), chronic myeloid leukemia (K562), prostate (PC-3), and hepatoma (Hep-G2) by methyl thiazolyl tetrazolium (MTT) colorimetric assay. Among these, compound 6o exhibited a promising inhibitory effect against the K562 cell line with the IC50 (50% inhibition concentration) value of 5.15 µM, and this compound showed great selectivity for normal cell (HEK-293, IC50 = 33.2 µM). Moreover, compound 6o was confirmed to affect apoptosis and cell cycle possibly by inhibiting Bcl2 family members and the p53/MDM2 pathway in a concentration-dependent manner. Overall, this study indicates that compound 6o could be a promising scaffold to develop an effective and low-toxic anticancer agent.
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Affiliation(s)
- Congyu Wang
- College of Pharmacy, Guizhou University, Guiyang 550025, China
- Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang 550025, China
| | - Mei Zhu
- Center for Research and Development of Fine Chemicals, Guizhou University, Guiyang 550025, China
| | - Xuesha Long
- College of Pharmacy, Guizhou University, Guiyang 550025, China
- Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang 550025, China
| | - Qin Wang
- College of Pharmacy, Guizhou University, Guiyang 550025, China
- Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang 550025, China
| | - Zhenchao Wang
- College of Pharmacy, Guizhou University, Guiyang 550025, China
- Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang 550025, China
- Center for Research and Development of Fine Chemicals, Guizhou University, Guiyang 550025, China
| | - Guiping Ouyang
- College of Pharmacy, Guizhou University, Guiyang 550025, China
- Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang 550025, China
- Center for Research and Development of Fine Chemicals, Guizhou University, Guiyang 550025, China
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20
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Kannan MP, Sreeraman S, Somala CS, Kushwah RB, Mani SK, Sundaram V, Thirunavukarasou A. Advancement of targeted protein degradation strategies as therapeutics for undruggable disease targets. Future Med Chem 2023; 15:867-883. [PMID: 37254917 DOI: 10.4155/fmc-2023-0072] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 05/10/2023] [Indexed: 06/01/2023] Open
Abstract
Targeted protein degradation (TPD) aids in developing novel bifunctional small-molecule degraders and eliminates proteins of interest. The TPD approach shows promising results in oncological, neurogenerative, cardiovascular and gynecological drug development. We provide an overview of technology advancements in TPD, including molecular glues, proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimeras, antibody-based PROTAC, GlueBody PROTAC, autophagy-targeting chimera, autophagosome-tethering compound, autophagy-targeting chimera and chaperone-mediated autophagy-based degraders. Here we discuss the development and evolution of the TPD field, the variety of proteins that PROTACs target and the biological repercussions of their degradation. We particularly highlight the recent improvements in TPD research that utilize autophagy or the endolysosomal pathway, which enables the targeting of undruggable targets.
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Affiliation(s)
- Mayuri P Kannan
- Department of Biotechnology, Saveetha School of Engineering, Saveetha Institute of Medical & Technical Sciences (SIMATS), Thandalam, Chennai, Tamil Nadu, 602105, India
- B-Aatral Biosciences Private Limited, Bangalore, Karnataka, 560091, India
| | - Sarojini Sreeraman
- Department of Biotechnology, Saveetha School of Engineering, Saveetha Institute of Medical & Technical Sciences (SIMATS), Thandalam, Chennai, Tamil Nadu, 602105, India
- SRIIC Lab, Sri Ramachandra Institute for Higher Education & Research, Chennai, Tamil Nadu, 600116, India
| | - Chaitanya S Somala
- B-Aatral Biosciences Private Limited, Bangalore, Karnataka, 560091, India
| | - Raja Bs Kushwah
- B-Aatral Biosciences Private Limited, Bangalore, Karnataka, 560091, India
- Department of Entomology and Agrilife Research, Texas A&M University, College Station, TX 77843, USA
| | - Saravanan K Mani
- B-Aatral Biosciences Private Limited, Bangalore, Karnataka, 560091, India
- Department of Biotechnology, Bharath Institute of Higher Education and Research, Chennai, Tamil Nadu, 600073, India
| | - Vickram Sundaram
- Department of Biotechnology, Saveetha School of Engineering, Saveetha Institute of Medical & Technical Sciences (SIMATS), Thandalam, Chennai, Tamil Nadu, 602105, India
| | - Anand Thirunavukarasou
- B-Aatral Biosciences Private Limited, Bangalore, Karnataka, 560091, India
- SRIIC Lab, Sri Ramachandra Institute for Higher Education & Research, Chennai, Tamil Nadu, 600116, India
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21
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Mehri A, Mardanshahi M, Sirous H, Khanahmad H, Rostami M. Pyrimido[4,5-b]indole derivatives bearing 1,2,4-oxadiazole moiety as MDM2 inhibitor candidates in cancer treatment. Future Med Chem 2023; 15:517-532. [PMID: 37097083 DOI: 10.4155/fmc-2023-0012] [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] [Indexed: 04/26/2023] Open
Abstract
Aim: In this study, novel hybrid structures of pyrimido-indole-oxadiazole were developed as MDM2 inhibitors for restoring the regular function of the p53. Materials & methods: A multistep chemical pathway was used to synthesize the derivatives. Nutlin-3a was used as a standard lead in molecular docking and molecular dynamics simulations. Finally, cytotoxicity was evaluated against MCF-7 cancer cells versus Doxorubicin. Results: The most promising candidate was 12c, which had an NO2 group in the para position of the oxadiazole ring (IC50: 1.1 μM). A satisfactory result was obtained with the combined application of 12c and Doxorubicin (IC50 decreased to 0.63 μM), which could be potentially attributed to MDM2 inhibition. Conclusion: These hybrid structures can be further investigated as potential MDM2 inhibitors.
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Affiliation(s)
- Ali Mehri
- Department of Medicinal Chemistry, School of Pharmacy & Pharmaceutical Science, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
| | - Mahboubeh Mardanshahi
- Department of Medicinal Chemistry, School of Pharmacy & Pharmaceutical Science, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
| | - Hajar Sirous
- Bioinformatics Research Center, School of Pharmacy & Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
| | - Hossein Khanahmad
- Department of Genetics & Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
| | - Mahboubeh Rostami
- Isfahan Pharmaceutical Sciences Research Center & Department of Medicinal Chemistry, School of Pharmacy & Pharmaceutical Science, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
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22
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Wang X, Liu Y, Li K, Hao Z. Roles of p53-Mediated Host–Virus Interaction in Coronavirus Infection. Int J Mol Sci 2023; 24:ijms24076371. [PMID: 37047343 PMCID: PMC10094438 DOI: 10.3390/ijms24076371] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/22/2023] [Accepted: 03/27/2023] [Indexed: 03/30/2023] Open
Abstract
The emergence of the SARS-CoV-2 coronavirus has garnered global attention due to its highly pathogenic nature and the resulting health crisis and economic burden. Although drugs such as Remdesivir have been considered a potential cure by targeting the virus on its RNA polymerase, the high mutation rate and unique 3’ to 5’ exonuclease with proofreading function make it challenging to develop effective anti-coronavirus drugs. As a result, there is an increasing focus on host–virus interactions because coronaviruses trigger stress responses, cell cycle changes, apoptosis, autophagy, and the dysregulation of immune function and inflammation in host cells. The p53 tumor suppressor molecule is a critical regulator of cell signaling pathways, cellular stress responses, DNA repair, and apoptosis. However, viruses can activate or inhibit p53 during viral infections to enhance viral replication and spread. Given its pivotal role in cell physiology, p53 represents a potential target for anti-coronavirus drugs. This review aims to summarize the relationship between p53 and coronaviruses from various perspectives, to shed light on potential targets for antiviral drug development and vaccine design.
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Affiliation(s)
| | | | | | - Zhihui Hao
- Correspondence: ; Tel./Fax: +86-010-6273-1192
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23
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Structure-based discovery of novel α-aminoketone derivatives as dual p53-MDM2/MDMX inhibitors for the treatment of cancer. Eur J Med Chem 2023; 252:115282. [PMID: 36989812 DOI: 10.1016/j.ejmech.2023.115282] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/12/2023] [Accepted: 03/12/2023] [Indexed: 03/17/2023]
Abstract
The function of the p53 protein is impaired by the overexpression of its negative regulator murine double minute 2 protein (MDM2) and homologous protein MDMX. Disruption of the p53-MDM2/MDMX interaction to restore the transcriptional function of p53 is considered a promising strategy for cancer therapy. To design dual MDM2/MDMX inhibitors, the binding modes of MDM2 or MDMX with their inhibitors are elucidated. Several hot-spot residues of MDM2 or MDMX are identified by molecular dynamics simulations, alanine scanning and MM-GBSA calculations. Then, focusing on the interaction with hot-spot residues, two series of derivatives bearing 1,3-diketone and α-aminoketone scaffolds are designed and synthesized. Among these compounds, C16 is identified as the most potent compound with low micromolar binding affinities with MDM2 and MDMX. C16 also displays moderate antiproliferative activities against MDM2-overexpressing and MDMX-overexpressing cells, with IC50 values of 0.68 μM in HCT116 cells and 0.54 μM in SH-SY5Y cells. Furthermore, C16 inhibits cell migration and invasion, reactivates the function of p53, arrests the cell cycle and induces cellular apoptosis in HCT116 and SH-SY5Y cells. Collectively, C16 can be developed as a dual MDM2 and MDMX inhibitor for cancer therapy.
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24
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Izmest'ev AN, Kravchenko AN, Gazieva GA. A new reversible transformation of oxindolylidene derivatives of imidazothiazolotriazine into 3-[(imidazotriazin-3-yl)thio]-2-oxoquinoline-4-carboxylates. Org Biomol Chem 2023; 21:1827-1834. [PMID: 36751947 DOI: 10.1039/d2ob02242g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
A simple method for the synthesis of water-soluble potassium 3-[(imidazotriazin-3-yl)thio]-2-oxoquinoline-4-carboxylates was developed based on a new reversible transformation of oxindolylidene derivatives of imidazothiazolotriazine that results from their treatment with potassium hydroxide. The antiproliferative activity of the synthesized compounds was evaluated against 58 cell lines and compared with oxindolylidene derivatives of imidazothiazolotriazine. Quinoline derivatives 3 demonstrated high activity with average GI50 values of <10 μM which are comparable or higher than those of the oxindolylidene imidazothiazolotriazines. Compound 3a, with a pent-3-yl substituent at the nitrogen atom of the quinoline fragment, possessed the highest antiproliferative activity with an average GI50 value of 1.71 μM. The GI50 values of compound 3a against 52 of the 58 cell lines were <1 μM; against the remaining 6 of the 58 cell lines, they were in the range 1.21-39.2 μM.
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Affiliation(s)
- Alexei N Izmest'ev
- N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prosp., 47, Moscow 119991, Russian Federation.
| | - Angelina N Kravchenko
- N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prosp., 47, Moscow 119991, Russian Federation.
| | - Galina A Gazieva
- N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prosp., 47, Moscow 119991, Russian Federation.
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25
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Chahat, Bhatia R, Kumar B. p53 as a potential target for treatment of cancer: A perspective on recent advancements in small molecules with structural insights and SAR studies. Eur J Med Chem 2023; 247:115020. [PMID: 36543034 DOI: 10.1016/j.ejmech.2022.115020] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/05/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022]
Abstract
Cancer represents one of the world's biggest hazardous diseases. p53 is the uttermost researched tumour suppressor protein. It is commonly considered the "guardian of the genome," performing a critical function in genetic stability maintenance through controlling the cell cycle, programmed cell death, DNA repair, aging, and angiogenesis. The abnormalities in p53 lead to genetic instability and plays a significant role in carcinogenesis. The role of p53 in tumour suppression is emphasized in addition by the observation that primary silencing with this protein occurred in more than 50% of cancers. MDM2, p53, and the p53-MDM2 connections are well-known targets for the prevention and treatment of cancer. Moreover, in tumors with wild-type p53, their efficacy is decreased due to MDM2 enlargement or by the gradual decrease of MDM2 blocker ARF. As a result, improving p53 activity in cancerous cells provides a promising anticancer strategy. Various techniques are now being investigated, and addressing the p53-MDM2 interaction had also evolved as a potentially feasible strategy for contending with tumors. Both p53 and MDM2, interact via an autoregulation response signal: p53 activity induces MDM2 transcription, which in response interacts with p53's N-terminal transactivation domain, inhibiting its transcriptional activity. This article provides information on the current scenario of anti-tumor activities, with a particular emphasis on structure-activity relationship characteristics (SAR) against the p53-MDM2 to treat cancer. The primary purpose of this review is to cover recent advancements in the creation and testing of anticancer drugs that target the p53-MDM2 structure. This review contains different heterocyclic moieties which show significant results toward cancer. A mechanistic route is shown here, demonstrating both normal and malignant conditions via several stressed factors. Several compounds entered clinical trials as p53-MDM2 inhibitors for the treatment of cancer.
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Affiliation(s)
- Chahat
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Ghal Kalan, Ferozpur G.T. Road MOGA, 142001, Punjab, India
| | - Rohit Bhatia
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Ghal Kalan, Ferozpur G.T. Road MOGA, 142001, Punjab, India
| | - Bhupinder Kumar
- Department of Pharmaceutical Sciences, HNB Garhwal University, Chauras Campus, Srinagar, Garhwal, Uttarakhand, 246174, India.
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26
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Patil MR, Bihari A. A comprehensive study of p53 protein. J Cell Biochem 2022; 123:1891-1937. [PMID: 36183376 DOI: 10.1002/jcb.30331] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 09/02/2022] [Accepted: 09/13/2022] [Indexed: 01/10/2023]
Abstract
The protein p53 has been extensively investigated since it was found 43 years ago and has become a "guardian of the genome" that regulates the division of cells by preventing the growth of cells and dividing them, that is, inhibits the development of tumors. Initial proof of protein existence by researchers in the mid-1970s was found by altering and regulating the SV40 big T antigen termed the A protein. Researchers demonstrated how viruses play a role in cancer by employing viruses' ability to create T-antigens complex with viral tumors, which was discovered in 1979 following a viral analysis and cancer analog research. Researchers later in the year 1989 explained that in Murine Friend, a virus-caused erythroleukemia, commonly found that p53 was inactivated to suggest that p53 could be a "tumor suppressor gene." The TP53 gene, encoding p53, is one of human cancer's most frequently altered genes. The protein-regulated biological functions of all p53s include cell cycles, apoptosis, senescence, metabolism of the DNA, angiogenesis, cell differentiation, and immunological response. We tried to unfold the history of the p53 protein, which was discovered long back in 1979, that is, 43 years of research on p53, and how p53's function has been developed through time in this article.
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Affiliation(s)
- Manisha R Patil
- Department of Computer-Applications, School of Information Technology and Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Anand Bihari
- Department of Computational Intelligence, School of Computer Science and Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu, India
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27
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Design and synthesis of novel cyclopeptide p53-MDM2 inhibitors with isoindolinone as antitumor agent. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.134604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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28
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Su Y, Sai Y, Zhou L, Liu Z, Du P, Wu J, Zhang J. Current insights into the regulation of programmed cell death by TP53 mutation in cancer. Front Oncol 2022; 12:1023427. [PMID: 36313700 PMCID: PMC9608511 DOI: 10.3389/fonc.2022.1023427] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 09/29/2022] [Indexed: 11/13/2022] Open
Abstract
Gene mutation is a complicated process that influences the onset and progression of cancer, and the most prevalent mutation involves the TP53 gene. One of the ways in which the body maintains homeostasis is programmed cell death, which includes apoptosis, autophagic cell death, pyroptosis, ferroptosis, NETosis, and the more recently identified process of cuprotosis. Evasion of these cell deaths is a hallmark of cancer cells, and our elucidation of the way these cells die helps us better understands the mechanisms by which cancer arises and provides us with more ways to treat it.Studies have shown that programmed cell death requires wild-type p53 protein and that mutations of TP53 can affect these modes of programmed cell death. For example, mutant p53 promotes iron-dependent cell death in ferroptosis and inhibits apoptotic and autophagic cell death. It is clear that TP53 mutations act on more than one pathway to death, and these pathways to death do not operate in isolation. They interact with each other and together determine cell death. This review focuses on the mechanisms via which TP53 mutation affects programmed cell death. Clinical investigations of TP53 mutation and the potential for targeted pharmacological agents that can be used to treat cancer are discussed.
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Affiliation(s)
- Yali Su
- Department of Clinical Laboratory, North China University of Science and Technology Affiliated Tangshan Maternal and Child Heath Care Hospital, Tangshan, China
| | - Yingying Sai
- Department of Clinical Laboratory, North China University of Science and Technology Affiliated Tangshan Maternal and Child Heath Care Hospital, Tangshan, China
| | - Linfeng Zhou
- Department of Clinical Laboratory, North China University of Science and Technology Affiliated Tangshan Maternal and Child Heath Care Hospital, Tangshan, China
| | - Zeliang Liu
- Department of Clinical Laboratory, North China University of Science and Technology Affiliated Hospital, Tangshan, China
| | - Panyan Du
- Department of Clinical Laboratory, North China University of Science and Technology Affiliated Tangshan Maternal and Child Heath Care Hospital, Tangshan, China
| | - Jinghua Wu
- Department of Clinical Laboratory, North China University of Science and Technology Affiliated Tangshan Maternal and Child Heath Care Hospital, Tangshan, China
- *Correspondence: Jinghua Wu, ; Jinghua Zhang,
| | - Jinghua Zhang
- Department of Clinical Laboratory, North China University of Science and Technology Affiliated Tangshan Maternal and Child Heath Care Hospital, Tangshan, China
- *Correspondence: Jinghua Wu, ; Jinghua Zhang,
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29
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Luo Z, Xu L, Tang X, Zhao X, He T, Lubell WD, Zhang J. Synthesis and biological evaluation of novel all-hydrocarbon cross-linked aza-stapled peptides. Org Biomol Chem 2022; 20:7963-7971. [PMID: 36190455 DOI: 10.1039/d2ob01496c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Novel all-hydrocarbon cross-linked aza-stapled peptides were designed and synthesized for the first time by ring-closing metathesis between two aza-alkenylglycine residues. Three aza-stapled peptidic analogues based on the peptide dual inhibitor of p53-MDM2/MDMX interactions were synthesized and screened for biological activities. Among the three aza-stapled peptides, aSPDI-411 displayed increased anti-tumor activity, binding affinities to both MDM2 and MDMX, and cell membrane permeability compared to its linear peptide counterpart.
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Affiliation(s)
- Zhihong Luo
- Innovative Drug Research Centre (IDRC), Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, P. R. China.
| | - Lei Xu
- Innovative Drug Research Centre (IDRC), Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, P. R. China.
| | - Xiaomin Tang
- Innovative Drug Research Centre (IDRC), Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, P. R. China.
| | - Xuejun Zhao
- Innovative Drug Research Centre (IDRC), Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, P. R. China.
| | - Tong He
- Innovative Drug Research Centre (IDRC), Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, P. R. China.
| | - William D Lubell
- Département de Chimie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec H3C 3J7, Canada.
| | - Jinqiang Zhang
- Innovative Drug Research Centre (IDRC), Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, P. R. China. .,Chongqing University Industrial Technology Research Institute, Chongqing 401329, People's Republic of China
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Anticancer Therapeutic Strategies Targeting p53 Aggregation. Int J Mol Sci 2022; 23:ijms231911023. [PMID: 36232329 PMCID: PMC9569952 DOI: 10.3390/ijms231911023] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/10/2022] [Accepted: 09/13/2022] [Indexed: 11/17/2022] Open
Abstract
p53 is a tumor suppressor protein that is mutated in more than 50% of cancer cases. When mutated, it frequently results in p53 oncogenic gain of function (GOF), resulting in a greater tendency to aggregate in the phase separation and phase transition pathway. GOFs related to p53 aggregation include chemoresistance, which makes therapy even more difficult. The therapies available for the treatment of cancer are still quite limited, so the study of new molecules and therapeutic targets focusing on p53 aggregates is a promising strategy against cancer. In this review, we classify anticancer molecules with antiaggregation properties into four categories: thiol alkylating agents, designed peptides, agents with chaperone-based mechanisms that inhibit p53 aggregation, and miscellaneous compounds with anti-protein aggregation properties that have been studied in neurodegenerative diseases. Furthermore, we highlight autophagy as a possible degradation pathway for aggregated p53. Here, considering cancer as a protein aggregation disease, we review strategies that have been used to disrupt p53 aggregates, leading to cancer regression.
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31
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Srdanović S, Wolter M, Trinh CH, Ottmann C, Warriner SL, Wilson AJ. Understanding the interaction of 14-3-3 proteins with hDMX and hDM2: a structural and biophysical study. FEBS J 2022; 289:5341-5358. [PMID: 35286747 PMCID: PMC9541495 DOI: 10.1111/febs.16433] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/11/2022] [Accepted: 03/11/2022] [Indexed: 01/06/2023]
Abstract
p53 plays a critical role in regulating diverse biological processes: DNA repair, cell cycle arrest, apoptosis and senescence. The p53 pathway has therefore served as the focus of multiple drug-discovery efforts. p53 is negatively regulated by hDMX and hDM2; prior studies have identified 14-3-3 proteins as hDMX and hDM2 client proteins. 14-3-3 proteins are adaptor proteins that modulate localization, degradation and interactions of their targets in response to phosphorylation. Thus, 14-3-3 proteins may indirectly modulate the interaction between hDMX or hDM2 and p53 and represent potential targets for modulation of the p53 pathway. In this manuscript, we report on the biophysical and structural characterization of peptide/protein interactions that are representative of the interaction between 14-3-3 and hDMX or hDM2. The data establish that proximal phosphosites spaced ~20-25 residues apart in both hDMX and hDM2 co-operate to facilitate high-affinity 14-3-3 binding and provide structural insight that can be utilized in future stabilizer/inhibitor discovery efforts.
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Affiliation(s)
- Sonja Srdanović
- Astbury Centre for Structural Molecular BiologyUniversity of LeedsUK,School of ChemistryUniversity of LeedsUK
| | - Madita Wolter
- Laboratory of Chemical BiologyDepartment of Biomedical EngineeringTechnische Universiteit EindhovenThe Netherlands,Institute for Complex Molecular SystemsTechnische Universiteit EindhovenThe Netherlands
| | - Chi H. Trinh
- Astbury Centre for Structural Molecular BiologyUniversity of LeedsUK,School of Molecular and Cellular BiologyUniversity of LeedsUK
| | - Christian Ottmann
- Laboratory of Chemical BiologyDepartment of Biomedical EngineeringTechnische Universiteit EindhovenThe Netherlands,Institute for Complex Molecular SystemsTechnische Universiteit EindhovenThe Netherlands
| | - Stuart L. Warriner
- Astbury Centre for Structural Molecular BiologyUniversity of LeedsUK,School of ChemistryUniversity of LeedsUK
| | - Andrew J. Wilson
- Astbury Centre for Structural Molecular BiologyUniversity of LeedsUK,School of ChemistryUniversity of LeedsUK
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Peng F, Liao M, Qin R, Zhu S, Peng C, Fu L, Chen Y, Han B. Regulated cell death (RCD) in cancer: key pathways and targeted therapies. Signal Transduct Target Ther 2022; 7:286. [PMID: 35963853 PMCID: PMC9376115 DOI: 10.1038/s41392-022-01110-y] [Citation(s) in RCA: 412] [Impact Index Per Article: 137.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 02/07/2023] Open
Abstract
Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD). Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes.
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Affiliation(s)
- Fu Peng
- West China School of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Minru Liao
- West China School of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Rui Qin
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Shiou Zhu
- West China School of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Leilei Fu
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
| | - Yi Chen
- West China School of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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Liu X, Yao C, Tang Y, Liu X, Duan C, Wang C, Han F, Xiang Y, Wu L, Li Y, Ji A, Cai T. Role of p53 methylation in manganese-induced cyclooxygenase-2 expression in BV2 microglial cells. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 241:113824. [PMID: 36068751 DOI: 10.1016/j.ecoenv.2022.113824] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 06/14/2022] [Accepted: 06/27/2022] [Indexed: 05/21/2023]
Abstract
Manganese (Mn) is an essential cofactor for many enzymes and plays an important role in normal growth and development. However, excess exposure to manganese (Mn) may be an important environmental factor leading to neurodegeneration. The overexpression of microglial cyclooxygenase-2 (COX-2) plays a key role in neuroinflammation in neurodegenerative diseases. The existing data suggest that Mn can induce neuroinflammation by up-regulating COX-2 expression. However, the mechanisms involved in Mn-induced microglial COX-2 up-regulation remain to be determined. The aim of this study was to investigate the role of p53 in Mn-induced COX-2 expression in microglial cells. The results showed that Mn exposure induced the up-regulation of COX-2 and inhibited the expression of p53 in BV2 microglial cells. The addition of p53 activator and the over-expression of p53 blocked the expression of COX-2 and prostaglandin E2 (PGE2), a COX-2 downstream effector, induced by Mn. Further, Mn increased the methylation of p53 DNA in microglia, while the addition of demethylation reagent 5-Aza-dC enhanced the expression of p53 but decreased the expression of COX-2. These results suggested that Mn may inhibit p53 expression through induction of DNA methylation, which can further induce the expression of COX-2 in microglial cells.
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Affiliation(s)
- Xiaoling Liu
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Chunyan Yao
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yan Tang
- Experimental Teaching Center, School of Public Health, Southwest Medical University, Luzhou, China
| | - Xiaoyan Liu
- The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China
| | - Chenggang Duan
- Department of Pathophysiology, Southwest Medical University, Luzhou, China
| | - Chunmei Wang
- Experimental Teaching Center, School of Public Health, Southwest Medical University, Luzhou, China
| | - Fei Han
- Institute of Toxicology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ying Xiang
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Long Wu
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yafei Li
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ailing Ji
- Department of Preventive Medicine & Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing Medical and Pharmaceutical College, Chongqing, China.
| | - Tongjian Cai
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China.
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Wang J, Yang W, He X, Zhang Z, Zheng X. Assembling p53 Activating Peptide With CeO2 Nanoparticle to Construct a Metallo-Organic Supermolecule Toward the Synergistic Ferroptosis of Tumor. Front Bioeng Biotechnol 2022; 10:929536. [PMID: 35837547 PMCID: PMC9273839 DOI: 10.3389/fbioe.2022.929536] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 05/17/2022] [Indexed: 11/22/2022] Open
Abstract
Inducing lipid peroxidation and subsequent ferroptosis in cancer cells provides a potential approach for anticancer therapy. However, the clinical translation of such therapeutic agents is often hampered by ferroptosis resistance and acquired drug tolerance in host cells. Emerging nanoplatform-based cascade engineering and ferroptosis sensitization by p53 provides a viable rescue strategy. Herein, a metallo-organic supramolecular (Nano-PMI@CeO2) toward p53 restoration and subsequent synergistic ferroptosis is constructed, in which the radical generating module-CeO2 nanoparticles act as the core, and p53-activator peptide (PMI)-gold precursor polymer is in situ reduced and assembled on the CeO2 surface as the shell. As expected, Nano-PMI@CeO2 effectively reactivated the p53 signaling pathway in vitro and in vivo, thereby downregulating its downstream gene GPX4. As a result, Nano-PMI@CeO2 significantly inhibited tumor progression in the lung cancer allograft model through p53 restoration and sensitized ferroptosis, while maintaining favorable biosafety. Collectively, this work develops a tumor therapeutic with dual functions of inducing ferroptosis and activating p53, demonstrating a potentially viable therapeutic paradigm for sensitizing ferroptosis via p53 activation. It also suggests that metallo-organic supramolecule holds great promise in transforming nanomedicine and treating human diseases.
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Affiliation(s)
- Jingmei Wang
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Wenguang Yang
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Talent Highland, The First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, China
| | - Xinyuan He
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zhang Zhang
- General Surgery Department, Tang Du Hospital, The Fourth Military Medical University, Xi’an, China
- *Correspondence: Zhang Zhang, ; Xiaoqiang Zheng,
| | - Xiaoqiang Zheng
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- *Correspondence: Zhang Zhang, ; Xiaoqiang Zheng,
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35
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Application of In Silico Filtering and Isothermal Titration Calorimetry for the Discovery of Small Molecule Inhibitors of MDM2. Pharmaceuticals (Basel) 2022; 15:ph15060752. [PMID: 35745671 PMCID: PMC9230431 DOI: 10.3390/ph15060752] [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: 04/24/2022] [Revised: 06/13/2022] [Accepted: 06/14/2022] [Indexed: 02/01/2023] Open
Abstract
The initial discovery phase of protein modulators, which consists of filtering molecular libraries and in vitro direct binding validation, is central in drug discovery. Thus, virtual screening of large molecular libraries, together with the evaluation of binding affinity by isothermal calorimetry, generates an efficient experimental setup. Herein, we applied virtual screening for discovering small molecule inhibitors of MDM2, a major negative regulator of the tumor suppressor p53, and thus a promising therapeutic target. A library of 20 million small molecules was screened against an averaged model derived from multiple structural conformations of MDM2 based on published structures. Selected molecules originating from the computational filtering were tested in vitro for their direct binding to MDM2 via isothermal titration calorimetry. Three new molecules, representing distinct chemical scaffolds, showed binding to MDM2. These were further evaluated by exploring structure-similar chemical analogues. Two scaffolds were further evaluated by de novo synthesis of molecules derived from the initial molecules that bound MDM2, one with a central oxoazetidine acetamide and one with benzene sulfonamide. Several molecules derived from these scaffolds increased wild-type p53 activity in MCF7 cancer cells. These set a basis for further chemical optimization and the development of new chemical entities as anticancer drugs.
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36
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Wang S, Chen FE. Small-molecule MDM2 inhibitors in clinical trials for cancer therapy. Eur J Med Chem 2022; 236:114334. [DOI: 10.1016/j.ejmech.2022.114334] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 03/27/2022] [Accepted: 03/28/2022] [Indexed: 02/07/2023]
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Wang Q, Li J, Zhu J, Mao J, Duan C, Liang X, Zhu L, Zhu M, Zhang Z, Lin F, Guo R. Genome-wide CRISPR/Cas9 screening for therapeutic targets in NSCLC carrying wild-type TP53 and receptor tyrosine kinase genes. Clin Transl Med 2022; 12:e882. [PMID: 35692096 PMCID: PMC9189421 DOI: 10.1002/ctm2.882] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 04/21/2022] [Accepted: 05/03/2022] [Indexed: 11/25/2022] Open
Abstract
Background Targeted drugs have greatly improved the therapeutic outcome of non‐small cell lung cancer (NSCLC) patients compared with conventional chemotherapy, whereas about one‐third of patients are so far not suitable for targeted therapy due to lack of known driver oncogenes such as a mutated receptor tyrosine kinase (RTK) genes. In this study, we aimed to identify therapeutic targets for this subgroup of NSCLC patients. Methods We performed genome‐wide CRISPR/Cas9 screens in two NSCLC cell lines carrying wild‐type TP53 and receptor tyrosine kinase (wtTP53‐RTK) genes using a GeCKO v2.0 lentiviral library (containing 123411 sgRNAs and targeting 19050 genes). MAGeCKFlute was used to analyse and identify candidate genes. Genetic perturbation and pharmacological inhibition were used to validate the result in vitro and in vivo. Results The Genome‐wide CRISPR/Cas9 screening identified MDM2 as a potential therapeutic target for wtTP53‐RTK NSCLC. Genetic and pharmacological inhibition of MDM2 reduced cell proliferation and impaired tumour growth in the xenograft model, thus confirming the finding of the CRISPR/Cas9 screening. Moreover, treatment by a selective MDM2 inhibitor RG7388 triggered both cell cycle arrest and apoptosis in several NSCLC cell lines. Additionally, RG7388 and pemetrexed synergistically blocked the cell proliferation and growth of wtTP53‐RTK tumours but had limited effects for other genotypes. Conclusions We identified MDM2 as an essential gene and a potential therapeutic target in wtTP53‐RTK NSCLC via a genome‐wide CRISPR/Cas9 screening. For this subgroup, treatment by RG7388 alone or by its combination with pemetrexed resulted in significant tumour inhibition.
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Affiliation(s)
- Qianqian Wang
- Department of Oncologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Jun Li
- Department of Oncologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Jing Zhu
- Department of Oncologythe Affiliated Jiangning Hospital of Nanjing Medical UniversityNanjingChina
| | - Jiaqi Mao
- Department of Cell BiologySchool of Basic Medical SciencesInstitute for Brain Tumors & Key Laboratory of Rare Metabolic DiseasesNanjing Medical UniversityNanjingChina
| | - Chao Duan
- Department of Cell BiologySchool of Basic Medical SciencesInstitute for Brain Tumors & Key Laboratory of Rare Metabolic DiseasesNanjing Medical UniversityNanjingChina
| | - Xiao Liang
- Department of Oncologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Lingyun Zhu
- Department of Cell BiologySchool of Basic Medical SciencesInstitute for Brain Tumors & Key Laboratory of Rare Metabolic DiseasesNanjing Medical UniversityNanjingChina
| | - Mengyan Zhu
- Department of BioinformaticsNanjing Medical UniversityNanjingChina
| | - Zhihong Zhang
- Department of Pathologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Fan Lin
- Department of Cell BiologySchool of Basic Medical SciencesInstitute for Brain Tumors & Key Laboratory of Rare Metabolic DiseasesNanjing Medical UniversityNanjingChina
| | - Renhua Guo
- Department of Oncologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
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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.
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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
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Zhang S, Yan Z, Li Y, Gong Y, Lyu X, Lou J, Zhang D, Meng X, Zhao Y. Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells. J Med Chem 2022; 65:6207-6230. [PMID: 35420431 DOI: 10.1021/acs.jmedchem.2c00095] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Despite recent clinical progress in peptide-based dual inhibitors of MDM2/4, small-molecule ones with robust antitumor activities remain challenging. To tackle this issue, 31 (YL93) was structure-based designed and synthesized, which had MDM2/4 binding Ki values of 1.1 and 642 nM, respectively. In three MDM4-overexpressing cancer cell lines harboring wild-type p53, 31 shows improved cell growth inhibition activities compared to RG7388, an MDM2-selective inhibitor in late-stage clinical trials. Mechanistic studies show that 31 increased cellular protein levels of p53 and p21 and upregulated the expression of p53-targeted genes in RKO cells with MDM4 amplification. In addition, 31 induced cell-cycle arrest and apoptosis in western blot and flow cytometry assays. Taken together, dual inhibition of MDM2/4 by 31 elicited stronger antitumor activities in vitro compared to selective MDM2 inhibitors in wild-type p53 and MDM4-overexpressing cancer cells.
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Affiliation(s)
- Shiyan Zhang
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Ziqin Yan
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Yafang Li
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,Nano Science and Technology Institute, University of Science and Technology of China, Suzhou, Jiangsu 215123, China
| | - Yang Gong
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xilin Lyu
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Jianfeng Lou
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Daizhou Zhang
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
| | - Xiangjing Meng
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
| | - Yujun Zhao
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.,School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.,School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.,Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
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Tao S, Yang Y, Fan Y, Chu K, Sun J, Wu Q, Wang A, Wan J, Tian H. Melatonin protects against nonylphenol caused pancreatic β-cells damage through MDM2-P53-P21 axis. Toxicol Res (Camb) 2022; 11:391-401. [PMID: 35782637 PMCID: PMC9244227 DOI: 10.1093/toxres/tfac016] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 01/07/2022] [Accepted: 03/11/2021] [Indexed: 11/13/2022] Open
Abstract
Abstract
Nonylphenol (NP) is an endocrine disrupting chemical, which widely exists in environment and can result in multiple system dysfunction. Pancreas as one of the most important organs is sensitive to NP, while the detail toxic effect is still less studied. Previously, we unveiled nonylphenol causes pancreatic damage in rats, herein, we further explore the potential mechanism and seek protection strategy in vitro. Insulinoma (INS-1) cells exposed to NP were observed to suffer oxidative stress and mitochondrial dysfunction, as reflected by the abnormal levels of reactive oxygen species, malonic dialdehyde, superoxide dismutase, Ca2+, and mitochondrial membrane potential. Melatonin (MT) was found to alleviate NP-induced mitochondrial dysfunction and oxidative stress, further inhibit apoptosis and restore pancreas function. Mechanically, MT induced the MDM2-P53-P21 signaling, which upregulated the Nrf2 signaling pathway. In summary, our study clarified NP-induced INS-1 cells mitochondrial dysfunction and oxidative stress, which could be ameliorated by MT through MDM2-P53-P21 axis.
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Affiliation(s)
- Shasha Tao
- Department of Occupational and Environmental Health, School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
- Department of Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Youjing Yang
- Department of Occupational and Environmental Health, School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Yayun Fan
- Yancheng First People’s Hospital, Yancheng, P. R. China
| | - Kaimiao Chu
- Department of Occupational and Environmental Health, School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Jiaojiao Sun
- Department of Occupational and Environmental Health, School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Qianqian Wu
- Department of Occupational and Environmental Health, School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Aiqing Wang
- Department of Experimental Center, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Jianmei Wan
- Department of Experimental Center, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Hailin Tian
- Department of Occupational and Environmental Health, School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
- Department of Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
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Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core. Pharmaceuticals (Basel) 2022; 15:ph15040444. [PMID: 35455441 PMCID: PMC9027661 DOI: 10.3390/ph15040444] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/23/2022] [Accepted: 03/26/2022] [Indexed: 11/25/2022] Open
Abstract
The use of p53-MDM2 inhibitors is a prospective strategy in anti-cancer therapy for tumors expressing wild type p53 protein. In this study, we have applied a simple approach of two-step synthesis of imidazoline-based alkoxyaryl compounds, which are able to efficiently inhibit p53-MDM2 protein–protein interactions, promote accumulation of p53 and p53-inducible proteins in various cancer cell lines. Compounds 2l and 2k cause significant upregulation of p53 and p53-inducible proteins in five human cancer cell lines, one of which possesses overexpression of MDM2.
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Deng Y, Li Y, Wang Y, Sun S, Ma S, Jia P, Li W, Wang K, Yan W. Efficient enantioselective synthesis of CF2H-containing dispiro[benzo[b]thiophene-oxindole-pyrrolidine]s via organocatalytic cycloaddition. Org Chem Front 2022. [DOI: 10.1039/d1qo01392k] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
A novel kind of CF2H-containing dispiro[benzo[b]thiophene-oxindole-pyrrolidine] has been achieved via an organocatalyzed 1,3-dipole reaction.
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Affiliation(s)
- Yabo Deng
- The Institute of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China
| | - Yongzhen Li
- The Institute of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China
| | - Yalan Wang
- The Institute of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China
| | - Shuo Sun
- The Institute of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China
| | - Sichao Ma
- The Institute of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China
| | - Pengfei Jia
- The Institute of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China
| | - Wenguang Li
- The Institute of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China
| | - Kairong Wang
- The Institute of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China
| | - Wenjin Yan
- The Institute of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China
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Vuaroqueaux V, Hendriks HR, Al-Hasani H, Peille AL, Das S, Fiebig HH. Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers. NPJ Precis Oncol 2021; 5:96. [PMID: 34711913 PMCID: PMC8553758 DOI: 10.1038/s41698-021-00235-7] [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: 08/28/2020] [Accepted: 10/04/2021] [Indexed: 11/25/2022] Open
Abstract
MI-773 is a recently developed small-molecule inhibitor of the mouse double minute 2 (MDM2) proto-oncogene. Preclinical data on the anti-tumour activity of MI-773 are limited and indicate that tumour cell lines (CLs) with mutated TP53 are more resistant to MI-773 than wild type TP53. Here, we explored the compound's therapeutic potential in vitro using a panel of 274 annotated CLs derived from a diversity of tumours. MI-773 exhibited a pronounced selectivity and moderate potency, with anti-tumour activity in the sub-micromolar range in about 15% of the CLs. The most sensitive tumour types were melanoma, sarcoma, renal and gastric cancers, leukaemia, and lymphoma. A COMPARE analysis showed that the profile of MI-773 was similar to that of Nutlin-3a, the first potent inhibitor of p53-MDM2 interactions, and, in addition, had a superior potency. In contrast, it poorly correlates with profiles of compounds targeting the p53 pathway with another mechanism of action. OMICS analyses confirmed that MI-773 was primarily active in CLs with wild type TP53. In silico biomarker investigations revealed that the TP53 mutation status plus the aggregated expression levels of 11 genes involved in the p53 signalling pathway predicted sensitivity or resistance of CLs to inhibitors of p53-MDM2 interactions reliably. The results obtained for MI-773 could help to refine the selection of cancer patients for therapy.
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Affiliation(s)
| | - Hans R Hendriks
- Hendriks Pharmaceutical Consulting, 1443 LR, Purmerend, The Netherlands
| | - Hoor Al-Hasani
- 4HF Biotec GmbH, Am Flughafen 14, 79108, Freiburg, Germany
| | | | - Samayita Das
- 4HF Biotec GmbH, Am Flughafen 14, 79108, Freiburg, Germany
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RNF2 promotes the progression of colon cancer by regulating ubiquitination and degradation of IRF4. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1869:119162. [PMID: 34670117 DOI: 10.1016/j.bbamcr.2021.119162] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 09/18/2021] [Accepted: 10/12/2021] [Indexed: 12/29/2022]
Abstract
Ring finger protein 2 (RNF2), as a well-known E3 ligase, has an oncogenic role in various cancers. The role of RNF2 in colon cancer is still unknown. The aim of this work is to determine the biological role of RNF2 in colon cancer. We first examined the expression of RNF2 and interferon regulatory factor 4 (IRF4) in colon cancer patients and colon cancer cell lines (SW480 and HCT116). Compared with normal tumor-adjacent tissues, RNF2 was up-regulated whereas IRF4 was down-regulated in the colon cancer tissues. RNF2 was also up-regulated in colon cancer cells with respect to human fetal colon epithelial cells. RNF2 overexpression enhanced the ability of proliferation, migration and invasion of SW480 cells, whereas RNF2 knockdown caused an opposite result in HCT116 cells. Furthermore, a tumor xenograft model was constructed to verify the impact of RNF2 overexpressed-SW480 cells on tumor growth. RNF2 up-regulation elevated Ki-67 proliferation index, accelerated the growth of tumor tissues, and led to severe colon tissue damage in the tumor xenograft mice. In addition, RNF2 interacted with IRF4, and repressed IRF4 protein expression. IRF4 was a substrate of RNF2, and RNF2 promoted the ubiquitination and degradation of IRF4. RNF2 overexpression increased the ability of proliferation, migration and invasion in SW480 cells by promoting the ubiquitination and degradation of IRF4. In conclusion, this work demonstrated that RNF2 promoted tumor growth in colon cancer by regulating ubiquitination and degradation of IRF4. Thus, RNF2 may be served as a potential therapeutic target for colon cancer.
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Bazanov DR, Pervushin NV, Savin EV, Tsymliakov MD, Maksutova AI, Sosonyuk SE, Kopeina GS, Lozinskaya NA. Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors. Med Chem Res 2021. [DOI: 10.1007/s00044-021-02802-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Hu J, Cao J, Topatana W, Juengpanich S, Li S, Zhang B, Shen J, Cai L, Cai X, Chen M. Targeting mutant p53 for cancer therapy: direct and indirect strategies. J Hematol Oncol 2021; 14:157. [PMID: 34583722 PMCID: PMC8480024 DOI: 10.1186/s13045-021-01169-0] [Citation(s) in RCA: 290] [Impact Index Per Article: 72.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 09/13/2021] [Indexed: 02/08/2023] Open
Abstract
TP53 is a critical tumor-suppressor gene that is mutated in more than half of all human cancers. Mutations in TP53 not only impair its antitumor activity, but also confer mutant p53 protein oncogenic properties. The p53-targeted therapy approach began with the identification of compounds capable of restoring/reactivating wild-type p53 functions or eliminating mutant p53. Treatments that directly target mutant p53 are extremely structure and drug-species-dependent. Due to the mutation of wild-type p53, multiple survival pathways that are normally maintained by wild-type p53 are disrupted, necessitating the activation of compensatory genes or pathways to promote cancer cell survival. Additionally, because the oncogenic functions of mutant p53 contribute to cancer proliferation and metastasis, targeting the signaling pathways altered by p53 mutation appears to be an attractive strategy. Synthetic lethality implies that while disruption of either gene alone is permissible among two genes with synthetic lethal interactions, complete disruption of both genes results in cell death. Thus, rather than directly targeting p53, exploiting mutant p53 synthetic lethal genes may provide additional therapeutic benefits. Additionally, research progress on the functions of noncoding RNAs has made it clear that disrupting noncoding RNA networks has a favorable antitumor effect, supporting the hypothesis that targeting noncoding RNAs may have potential synthetic lethal effects in cancers with p53 mutations. The purpose of this review is to discuss treatments for cancers with mutant p53 that focus on directly targeting mutant p53, restoring wild-type functions, and exploiting synthetic lethal interactions with mutant p53. Additionally, the possibility of noncoding RNAs acting as synthetic lethal targets for mutant p53 will be discussed.
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Affiliation(s)
- Jiahao Hu
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, China
- School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Jiasheng Cao
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, China
- School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Win Topatana
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, China
- School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | | | - Shijie Li
- School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Bin Zhang
- School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Jiliang Shen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, China
| | - Liuxin Cai
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, China
| | - Xiujun Cai
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, China.
- School of Medicine, Zhejiang University, Hangzhou, 310058, China.
- Engineering Research Center of Cognitive Healthcare of Zhejiang Province, Zhejiang Province, Hangzhou, China.
- Key Laboratory of Endoscopic Technique Research of Zhejiang Province, No. 3 East Qingchun Road, Hangzhou, 310016, China.
| | - Mingyu Chen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, China.
- School of Medicine, Zhejiang University, Hangzhou, 310058, China.
- Engineering Research Center of Cognitive Healthcare of Zhejiang Province, Zhejiang Province, Hangzhou, China.
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Harakandi C, Nininahazwe L, Xu H, Liu B, He C, Zheng YC, Zhang H. Recent advances on the intervention sites targeting USP7-MDM2-p53 in cancer therapy. Bioorg Chem 2021; 116:105273. [PMID: 34474304 DOI: 10.1016/j.bioorg.2021.105273] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 08/10/2021] [Accepted: 08/14/2021] [Indexed: 01/29/2023]
Abstract
The ubiquitin-specific protease 7 (USP7)-murine double minute 2 (MDM2)-p53 network plays an important role in the regulation of p53, a tumor suppressor which plays critical roles in regulating cell growth, proliferation, cell cycle progression, apoptosis and immune response. The overexpression of USP7 and MDM2 in human cancers contributes to cancer initiation and progression, and their inhibition reactivates p53 signalings and causes cell cycle arrest and apoptosis. Herein, the current state of pharmacological characterization, potential applications in cancer treatment and mechanism of action of small molecules used to target and inhibit MDM2 and USP7 proteins are highlighted, along with the outcomes in clinical and preclinical settings. Moreover, challenges and advantages of these strategies, as well as perspectives in USP7-MDM2-p53 field are analyzed in detail. The investigation and application of MDM2 and USP7 inhibitors will deepen our understanding of the function of USP7-MDM2-p53 network, and feed in the development of effective and safe cancer therapies where USP7-MDM2-p53 network is implicated.
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Affiliation(s)
- Chrisanta Harakandi
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Lauraine Nininahazwe
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Haiwei Xu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Bingrui Liu
- College of Public Health, North China University of Science and Technology, Tangshan 063503, China
| | - Chenghua He
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Yi-Chao Zheng
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Hang Zhang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
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48
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Si D, Luo H, Zhang X, Yang K, Wen H, Li W, Liu J. Design, synthesis and biological evaluation of novel pyrrolidone-based derivatives as potent p53-MDM2 inhibitors. Bioorg Chem 2021; 115:105268. [PMID: 34426149 DOI: 10.1016/j.bioorg.2021.105268] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 07/28/2021] [Accepted: 08/11/2021] [Indexed: 11/16/2022]
Abstract
Inhibition of the interactions of the tumor suppressor protein p53 with its negative regulators MDM2 in vitro and in vivo, representing a valuable therapeutic strategy for cancer treatment. The natural product chalcone exhibited moderate inhibitory activity against MDM2, thus based on the binding mode between chalcone and MDM2, a hit unsaturated pyrrolidone scaffold was obtained through virtual screening. Several unsaturated pyrrolidone derivatives were synthesized and biological evaluated. As a result, because the three critical hydrophobic pockets of MDM2 were occupied by the substituted-phenyl linked at the pyrrolidone fragment, compound 4 h demonstrated good binding affinity with the MDM2. Additionally, compound 4 h also showed excellent antitumor activity and selectivity, and no cytotoxicity against normal cells in vitro. The further antitumor mechanism studies were indicated that compound 4 h could successfully induce the activation of p53 and corresponding downstream p21 proteins, thus successfully causing HCT116 cell cycle arrest in the G1/M phase and apoptosis. Thus, the novel unsaturated pyrrolidone p53-MDM2 inhibitors could be developed as novel antitumor agents.
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Affiliation(s)
- Dongjuan Si
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Huijuan Luo
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xiaomeng Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Kundi Yang
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA
| | - Hongmei Wen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Wei Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Jian Liu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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MDM2 amplification in malignant Brenner tumors may play a role in progression to malignancy and aid in separation from urothelial and other ovarian carcinomas. Hum Pathol 2021; 117:42-50. [PMID: 34391746 DOI: 10.1016/j.humpath.2021.08.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 11/20/2022]
Abstract
Malignant Brenner tumor (MBT) is diagnosed in the setting of invasive high-grade carcinoma with urothelial-like morphology and the presence of an adjacent benign Brenner tumor (BBT) or borderline Brenner tumor (BLBT). MDM2 amplification was recently detected by next-generation sequencing on a small number of MBTs, potentially significant for future targeted therapy. Experience is limited, however, and evaluation of widely available MDM2 immunohistochemistry (IHC) has not been performed to determine clinical utility. After confirming all diagnoses morphologically and immunohistochemically, we performed MDM2 IHC on 4 MBTs, 3 BLBTs, 26 BBTs, 142 high-grade serous carcinomas (HGSC), 6 ovarian endometrioid carcinomas (OEC) with urothelial-like morphology, and 49 high-grade urothelial carcinomas (HGUC). MDM2 IHC was considered positive with diffuse (>25%) nuclear reactivity; in cases of patchy staining (10-25% nuclear reactivity), MDM2 was considered equivocal. Positive staining in <10% of cells was considered negative. In cases with positive or equivocal staining, MDM2 amplification was evaluated by fluorescence in-situ hybridization (FISH). Three MBTs (75%) showed diffuse nuclear reactivity for MDM2 by IHC, a finding corroborated by amplification of MDM2 in all three cases. One MBT and 2 BLBTs showed equivocal MDM2 IHC, but all three were negative for MDM2 amplification. The final BLBT, as well as all BBTs, HGSC, OEC, and HGUC, were negative for MDM2. In conclusion, our limited cohort confirms MDM2 amplification in MBT and suggests that MDM2 IHC may have an influence in rare diagnostically challenging cases.
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50
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Unleashing the power of NK cells in anticancer immunotherapy. J Mol Med (Berl) 2021; 100:337-349. [PMID: 34374809 PMCID: PMC8843917 DOI: 10.1007/s00109-021-02120-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/15/2021] [Accepted: 07/16/2021] [Indexed: 12/12/2022]
Abstract
Due to their physiological role in removing damaged cells, natural killer (NK) cells represent ideal candidates for cellular immunotherapy in the treatment of cancer. Thereby, the cytotoxicity of NK cells is regulated by signals on both, the NK cells as well as the targeted tumor cells, and the interplay and balance of these signals determine the killing capacity of NK cells. One promising avenue in cancer treatment is therefore the combination of NK cell therapy with agents that either help to increase the killing capacity of NK cells or sensitize tumor cells to an NK cell-mediated attack. In this mini-review, we present different strategies that can be explored to unleash the potential of NK cell immunotherapy. In particular, we summarize how modulation of apoptosis signaling within tumor cells can be exploited to sensitize tumor cells to NK cell-mediated cytotoxicity.
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