Drugging p53 mutants: Recent advances using small-molecule modulation strategies

TP53 is the most frequently mutated gene in human cancers, with hundreds of mutations leading to loss of p53 tumor-suppressive functions. p53 mutations are closely associated with tumor progression, metastasis, and therapy resistance. In recent years, significant progress has been made in developing small-molecules targeting mutant (mut) p53 to restore its tumor suppressor activity. This review presents a comprehensive and updated overview on the recent advances in small-molecule mut p53 modulators reported between 2020 and 2025. This review distinguishes itself by focusing on the different modulation mechanisms of mut p53 reactivation, including covalent electrophiles, metal-based coordinators, selective reversible non-covalent modulators, as well as chemical inducers of proximity (CIP). We also highlight past and current key clinical candidates and emerging compounds, discuss their mechanisms of action, and consider their therapeutic potential in re-establishing p53's tumor-suppressor function in cancer, offering a forward-looking perspective on therapeutic development.