Drugging the “undruggable” p53: a structure-guided strategy against the Y220C mutation

Abstract

Abstract Tumor Protein p53 (TP53) is the most frequently altered gene in human cancer, yet mutant p53 has long been considered undruggable. The Y220C mutation is exceptional because it both destabilizes the p53 DNA-binding domain (DBD) and creates a unique surface pocket absent in wild-type protein. Availability of structural information enabled structure-based development of rezatapopt (PC14586), which binds this neo-pocket, stabilizes mutant p53, and restores transcriptional tumor suppressor activity. Early clinical studies in the PYNNACLE trial provide proof-of-concept efficacy and reveal emerging on-target resistance. This success supports a broader paradigm in which oncogenic missense mutations can generate druggable neo-pockets, exemplified by KRAS G12C inhibitors such as sotorasib. While most p53 hotspot mutations lack such features, computational pocket detection and structure-guided design may expand targetability across the mutational landscape. Complementary strategies, including covalent stabilization and targeted degradation, further extend this framework, establishing mutation-encoded structural vulnerabilities as actionable therapeutic opportunities.