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

The paradigm-shifting nature of this discovery has been independently recognized as a “Model Revolution” by Research Square, underlining its significance in reclassifying mutant TP53 as druggable. https://preprintwatch.com/cracking-the-undruggable-discovery-of-a-mutation

Cracking the Undruggable: Discovery of a Mutation-Induced Cryptic Pocket in TP53 C238Y for Precision Oncology Stage Model Revolution Paradigm framing The established paradigm of mutant TP53 being "undruggable" due to a lack of stable binding pockets. Highlights 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. “While my in silico studies provide strong evidence for a C238Y‐specific cryptic pocket and selective umbraselib binding, functional confirmation in purified protein, cellular models, and biophysical assays remains essential. To bridge this gap, i are actively seeking academic and industry partners with expertise in biophysical characterization (e.g., ITC, SPR, X-ray crystallography) and TP53 C238Y cellular models. Such collaborations will accelerate experimental validation, optimize lead compounds, and lay the groundwork for downstream drug development.” • Computational work is solid but incomplete— already shown docking and MD data. • Specific experimental steps are needed—protein purification, binding assays, structural determination, cellular studies. • Partnerships bring resources and expertise—am looking for groups that can handle those assays or models. • The ultimate goal is drug development positioning the partnership as the logical next stage.