Related Experiment Video

Updated: Jun 2, 2025

Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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Discovery of Rezatapopt (PC14586), a First-in-Class, Small-Molecule Reactivator of p53 Y220C Mutant in Development

Binh T Vu1, Romyr Dominique1, Bruce J Fahr1

  • 1Discovery Chemistry, PMV Pharmaceuticals, Inc., 400 Alexander Park Drive, Suite 301, Princeton, New Jersey 08540, United States.

ACS Medicinal Chemistry Letters
|January 15, 2025
PubMed

Insights

Rezatapopt reactivates the Y220C mutant p53 protein, restoring its tumor suppressor function. This novel therapy shows promise in inhibiting and regressing tumors in preclinical models and early clinical trials.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The p53 protein is a critical regulator of cellular stress responses.
  • Mutations in the TP53 gene, particularly in the DNA-binding domain, are common in human cancers.
  • The TP53 Y220C mutation results in a thermally unstable p53 protein, compromising its function.

Purpose of the Study:

  • To evaluate rezatapapopt (PC14586), a novel small-molecule reactivator, for its ability to restore function to the Y220C mutant p53.
  • To assess the efficacy and safety of rezatapapopt in preclinical cancer models and Phase 1 clinical trials.

Main Methods:

  • Rezatapopt was designed to specifically bind to the pocket formed by the TP53 Y220C mutation.
  • Efficacy was evaluated in mouse xenograft models with human tumors harboring the TP53 Y220C mutation.
  • Phase 1 clinical trials assessed safety, tolerability, and single-agent efficacy in patients with TP53 Y220C mutant solid tumors.

Main Results:

  • Rezatapopt demonstrated tumor inhibition and regression in preclinical models at well-tolerated doses.
  • Phase 1 trials showed a favorable safety profile for rezatapapopt within efficacious dose ranges.
  • Rezatapopt exhibited single-agent efficacy in heavily pretreated patients with diverse TP53 Y220C mutant solid tumors.

Conclusions:

  • Rezatapopt effectively stabilizes the p53 protein structure, restoring its tumor suppressor activity.
  • Rezatapopt represents a promising therapeutic strategy for cancers harboring the TP53 Y220C mutation.
  • The drug's favorable safety and efficacy profile warrants further clinical investigation.

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