TP53 Y220C

This triple allosteric framework underscores the regulatory regions' critical role in restoring p53 functionality. By providing a first-order exploration into the behavior of full-length p53, this study advances our understanding of its regulatory mechanisms and sets the stage for developing targeted therapies aimed at reactivating mutant p53 in cancer.

Functional modeling confirmed these double mutants eliminate p53 reactivation and target gene induction by rezatapopt. These findings establish a molecular framework for resistance to p53 Y220C reactivators and inform strategies to overcome resistance with next-generation agents.

Clinical proteomic analysis of platinum-resistant ovarian cancer tissues reveals tumor-specific factors and acquired resistance pathways linked to p53 mutations. Our findings elucidate the multilayered regulatory landscape of p53 mutations and identify potential risk factors for platinum resistance associated with these mutations.

This work establishes a mechanistic foundation for rational stabilizer design, proposing a new strategy centered on allosteric network restoration and mutation-adaptable anchoring. It offers broader implications for targeting conformationally unstable transcription factors previously considered "undruggable".

Our results demonstrated the viability of the DUBTAC strategy for p53 Y220C, successfully re-establishing conformation and promoting deubiquitination. More importantly, this study provides the first proof-of-concept for DUBTAC application in vivo, establishing targeted deubiquitination as a therapeutic approach.

Our findings position JC16 and JC36 as early-stage chemical leads with potential to restore mutant p53 function in a context-dependent manner. While their exact mechanism of action remains to be fully elucidated, these results provide a foundation for further development of indazole-based scaffolds as reactivators of the p53-Y220C mutant in cancer therapy.

In this work, we show that missense mutant forms of p53, which occur in >60% of HGSOC, bind and inhibit ERα function and confer resistance to fulvestrant and elacestrant. Mechanistically, we show that mutant p53 predominantly inhibits one arm of the ERα pathway-the transactivation of jointly regulated ERα-SP1 target genes such as the mTOR regulator DEPTOR We show that silencing mutant p53 restores the ability of ERα to transactivate ERα-SP1 target genes and renders HGSOC markedly more sensitive to endocrine therapy. Consistent with this premise, we show that the p53 mutant Y220C refolding compound rezatapopt enhances fulvestrant response in a Y220C mutant cell line.

The resulting bifunctional molecule promotes formation of a p53Y220C-PLK1 ternary complex, mislocalizes PLK1, inhibits PLK1 activity, elicits selective G2/M arrest and induces apoptosis in TP53Y220C cells while sparing wild-type TP53 cells. These data exemplify a potentially generalizable framework for targeting TP53 missense mutations by leveraging mutant p53 protein abundance to induce cell death, independent of p53's transcriptional activity.

P1/2, N=300, Recruiting, PMV Pharmaceuticals, Inc | N=230 --> 300 | Trial completion date: Jul 2026 --> Dec 2027 | Trial primary completion date: Mar 2026 --> Aug 2026

Overall, our study provides evidence that CGP significantly improves the identification of molecular targets in HGSOC, supporting its importance in the clinical practice to provide patients with more therapeutic options.

NCT04585750 (ClinicalTrials.gov).

P1, N=82, Not yet recruiting, Zhongshan Hospital, Fudan University; Zhongshan Hospital, Fudan University