Small-molecule correctors and stabilizers to target p53

The tumor suppressor p53 is the most frequently mutated protein in human can-cer and tops the list of high-value precision oncology targets. p53 prevents initi-ation 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.

Automated summary

The tumor suppressor p53 is frequently mutated in human cancer and is a high-value target for precision oncology. p53 prevents cancer by inducing cell-cycle arrest and cell death. Tumors have evolved mechanisms to inactivate p53, mainly through TP53 mutations or hyperactive degradation. This review focuses on MDM2 antagonists and mutant p53 correctors as p53-targeting compounds, discussing their mode of action and the challenges in advancing them to the clinic.