Small-molecule Correctors and Stabilizers to Target P53

Overview

Journal Trends Pharmacol Sci

Specialty Pharmacology

Date 2023 Mar 24

PMID 36964053

Authors

Maryam M J Fallatah

Fiona V Law

Warren A Chow

Peter Kaiser

Affiliations

Soon will be listed here.

Abstract

The tumor suppressor p53 is the most frequently mutated protein in human cancer and tops the list of high-value precision oncology targets. p53 prevents initiation and progression of cancer by inducing cell-cycle arrest and various forms of cell death. Tumors have thus evolved ways to inactivate p53, mainly by TP53 mutations or by hyperactive p53 degradation. This review focuses on two types of p53 targeting compounds, MDM2 antagonists and mutant p53 correctors. MDM2 inhibitors prevent p53 protein degradation, while correctors restore tumor suppressor activity of p53 mutants by enhancing thermodynamic stability. Herein we explore both novel and repurposed p53 targeting compounds, discuss their mode of action, and examine the challenges in advancing them to the clinic.

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References

Degtjarik O, Golovenko D, Diskin-Posner Y, Abrahmsen L, Rozenberg H, Shakked Z . Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ). Nat Commun. 2021; 12(1):7057. PMC: 8642532. DOI: 10.1038/s41467-021-27142-6. View

Zhu H, Gao H, Ji Y, Zhou Q, Du Z, Tian L . Targeting p53-MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials. J Hematol Oncol. 2022; 15(1):91. PMC: 9277894. DOI: 10.1186/s13045-022-01314-3. View

Joerger A, Fersht A . Structure-function-rescue: the diverse nature of common p53 cancer mutants. Oncogene. 2007; 26(15):2226-42. DOI: 10.1038/sj.onc.1210291. View

Zhu J, Sammons M, Donahue G, Dou Z, Vedadi M, Getlik M . Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature. 2015; 525(7568):206-11. PMC: 4568559. DOI: 10.1038/nature15251. View

Chen S, Wu J, Liang Y, Tang Y, Song H, Wu L . Arsenic Trioxide Rescues Structural p53 Mutations through a Cryptic Allosteric Site. Cancer Cell. 2020; 39(2):225-239.e8. DOI: 10.1016/j.ccell.2020.11.013. View

Wang B, Wu S, Liu J, Yang K, Xie H, Tang W . Development of selective small molecule MDM2 degraders based on nutlin. Eur J Med Chem. 2019; 176:476-491. DOI: 10.1016/j.ejmech.2019.05.046. View

Aiken C, Kaake R, Wang X, Huang L . Oxidative stress-mediated regulation of proteasome complexes. Mol Cell Proteomics. 2011; 10(5):R110.006924. PMC: 3098605. DOI: 10.1074/mcp.M110.006924. View

Blanden A, Yu X, Blayney A, Demas C, Ha J, Liu Y . Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants. Elife. 2020; 9. PMC: 7728444. DOI: 10.7554/eLife.61487. View

Tang Y, Song H, Wang Z, Xiao S, Xiang X, Zhan H . Repurposing antiparasitic antimonials to noncovalently rescue temperature-sensitive p53 mutations. Cell Rep. 2022; 39(2):110622. DOI: 10.1016/j.celrep.2022.110622. View

10.

Ray-Coquard I, Blay J, Italiano A, Cesne A, Penel N, Zhi J . Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 2012; 13(11):1133-40. DOI: 10.1016/S1470-2045(12)70474-6. View

11.

Sun D, Li Z, Rew Y, Gribble M, Bartberger M, Beck H . Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem. 2014; 57(4):1454-72. DOI: 10.1021/jm401753e. View

12.

Fujihara K, Corrales Benitez M, Cabalag C, Zhang B, Ko H, Liu D . SLC7A11 Is a Superior Determinant of APR-246 (Eprenetapopt) Response than Mutation Status. Mol Cancer Ther. 2021; 20(10):1858-1867. DOI: 10.1158/1535-7163.MCT-21-0067. View

13.

Khoo K, Andreeva A, Fersht A . Adaptive evolution of p53 thermodynamic stability. J Mol Biol. 2009; 393(1):161-75. DOI: 10.1016/j.jmb.2009.08.013. View

14.

Shimada K, Reznik E, Stokes M, Krishnamoorthy L, Bos P, Song Y . Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells. Cell Chem Biol. 2018; 25(5):585-594.e7. PMC: 5959763. DOI: 10.1016/j.chembiol.2018.02.010. View

15.

de The H, Pandolfi P, Chen Z . Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure. Cancer Cell. 2017; 32(5):552-560. DOI: 10.1016/j.ccell.2017.10.002. View

16.

Zhou S, Fan C, Zeng Z, Young K, Li Y . Clinical and Immunological Effects of p53-Targeting Vaccines. Front Cell Dev Biol. 2021; 9:762796. PMC: 8595300. DOI: 10.3389/fcell.2021.762796. View

17.

Bykov V, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P . Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med. 2002; 8(3):282-8. DOI: 10.1038/nm0302-282. View

18.

Joerger A, Ang H, Fersht A . Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. Proc Natl Acad Sci U S A. 2006; 103(41):15056-61. PMC: 1635156. DOI: 10.1073/pnas.0607286103. View

19.

Chen S, Li X, Li Y, Yuan X, Geng C, Gao S . Design of stapled peptide-based PROTACs for MDM2/MDMX atypical degradation and tumor suppression. Theranostics. 2022; 12(15):6665-6681. PMC: 9516243. DOI: 10.7150/thno.75444. View

20.

Olivier M, Eeles R, Hollstein M, Khan M, Harris C, Hainaut P . The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat. 2002; 19(6):607-14. DOI: 10.1002/humu.10081. View