Small-molecule correctors and stabilizers to target p53.

The tumor suppressor p53 is among the most attractive precision oncology targets. The two main small-molecule-based approaches for targeting p53 are blocking degradation of wild-type p53 and reactivating mutant p53 with corrector drugs. MDM2 antagonists efficiently increase p53 protein levels and activate tumor suppression in preclinical settings, but clinical use may need combination therapy. Corrector molecules act through diverse mechanisms to stabilize a wild-type-like conformation in p53 mutants. Several cysteine residues in p53 play a crucial role in the mode of action for a number of compounds. Molecules binding to the same binding site can reactivate a different spectrum of p53 mutants. Early clinical reports using mutant p53 corrector drugs are promising, and the recent discovery of mutant p53 reactivator activities in FDA-approved drugs has accelerated clinical translation. 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. [ABSTRACT FROM AUTHOR]