Cracking the Undruggable: Discovery of a Mutation-Induced Cryptic Pocket in TP53 C238Y for Precision Oncology

TP53 has long been deemed “undruggable,” particularly in its mutant forms, due to the lack of stable, targetable pockets. In this study, I report the discovery of a cryptic binding pocket induced by the C238Y mutation in TP53—absent in the wild-type protein and formed through local loop flexibility. Using flexible docking, molecular dynamics simulations, and machine learning-based rescoring, I demonstrate that the small molecule umbrasilib binds selectively and stably within this cryptic groove. The site’s emergence was validated through structural overlays, contact frequency maps, hydrogen bonding analysis, and GNINA CNN scoring. Unlike previous TP53- targeting approaches that lacked specificity or relied on reactivation attempts, this work provides the first structure-based evidence of a mutation-specific druggable pocket in TP53. The findings mark a paradigm shift in mutant p53 targeting and establish a mechanistic and computational foundation for future drug discovery efforts against cryptic oncogenic conformations.