Small-molecule correctors and stabilizers to target p53.

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.
Competing Interests: Declaration of interests P.K. is listed as inventor on the following patents, which describe molecules involved in p53 reactivation. Amaro, R.E. et al.: Small molecules to enhance p53 activity. US20160193214 A1. Luecke, H. et al. Small molecules for restoring function to p53 cancer mutants, US20150307519 A1. Kaiser, P. et al. Methods and compositions for treating cancer using small molecules that reactivate p53, provisional patent, UC Case 2020-611 (pending).
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