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

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.