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

The established paradigm of mutant TP53 being "undruggable" due to a lack of stable binding pockets.

This preprint presents compelling computational evidence challenging the current paradigm by demonstrating the existence of a mutation-induced cryptic pocket in the TP53 C238Y mutant. While the in silico findings are robust and suggest a paradigm shift, the lack of experimental validation warrants classifying this work as a model revolution. The research provides a strong mechanistic and structural basis for the druggability of this TP53 mutant, paving the way for future experimental studies and drug development efforts. The detailed molecular dynamics simulations, docking studies, and interaction analysis strongly support the formation and ligandability of this cryptic pocket, offering a new perspective for targeting previously considered undruggable cancer targets. However, further experimental evidence is needed to definitively confirm a full paradigm shift.