2. Academic Validation
  3. Discovery of Rezatapopt (PC14586), a First-in-Class, Small-Molecule Reactivator of p53 Y220C Mutant in Development

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

  • ACS Med Chem Lett. 2024 Nov 4;16(1):34-39. doi: 10.1021/acsmedchemlett.4c00379.
Binh T Vu 1,  Romyr Dominique 1,  Bruce J Fahr 1,  Hongju H Li 1,  David C Fry 2,  Lizhong Xu 3,  Hong Yang 3,  Anna Puzio-Kuter 3,  Andrew Good 4,  Binbin Liu 5,  Kuo-Sen Huang 6,  Naoko Tanaka 6,  Thomas W Davis 3,  Melissa L Dumble 3
Affiliations

Affiliations

  • 1 Discovery Chemistry, PMV Pharmaceuticals, Inc., 400 Alexander Park Drive, Suite 301, Princeton, New Jersey 08540, United States.
  • 2 The Chemistry Research Solution, 360 George Patterson Blvd., Suite 108, Bristol, Pennsylvania 19007, United States.
  • 3 Discovery Biology, PMV Pharmaceuticals, Inc., 400 Alexander Park Drive, Suite 301, Princeton, New Jersey 08540, United States.
  • 4 CAnDiD Consulting, 52 High Hill Road, Wallingford, Connecticut 06492, United States.
  • 5 WuXi AppTec (Tianjin) Co., 168 Nanhai Road, Tianjin 300457, China.
  • 6 Cepter Biopartners, 123 Metro Boulevard, Nutley, New Jersey 07110, United States.
PMID: 39811143 DOI: 10.1021/acsmedchemlett.4c00379
Abstract

p53 is a potent transcription factor that is crucial in regulating cellular responses to stress. Mutations in the TP53 gene are found in >50% of human cancers, predominantly occurring in the DNA-binding domain (Amino acids 94-292). The Y220C mutation accounts for 1.8% of all of the TP53 mutations and produces a thermally unstable protein. Rezatapopt (also known as PC14586) is the first small-molecule p53 Y220C reactivator being evaluated in clinical trials. Rezatapopt was specifically designed to tightly bind to a pocket created by the TP53 Y220C mutation. By stabilization of the p53 protein structure, rezatapopt restores p53 tumor suppressor functions. In mouse models with established human tumor xenografts harboring the TP53 Y220C mutation, rezatapopt demonstrated tumor inhibition and regression at well-tolerated doses. In Phase 1 clinical trials, rezatapopt demonstrated a favorable safety profile within the efficacious dose range and showed single-agent efficacy in heavily pretreated patients with various TP53 Y220C mutant solid tumors.

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