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. 2024 Nov 4;16(1):34-39.
doi: 10.1021/acsmedchemlett.4c00379. eCollection 2025 Jan 9.

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

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

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

Binh T Vu et al. ACS Med Chem Lett. .

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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Conflict of interest statement

The authors declare the following competing financial interest(s): Binh T. Vu, Romyr Dominique, Bruce J. Fahr, Hongju H. Li, Lizhong Xu, Hong Yang, Anna Puzio-Kuter, Thomas W. Davis, and Melissa L. Dumble are/were employees of PMV Pharmaceuticals (with stock options). Andrew Good, David C. Fry, Binbin Liu, Kuo-Sen Huang, and Naoko Tanaka declare no competing financial interest.

Figures

Figure 1
Figure 1
Early p53 Y220C mutant reactivator compounds.
Figure 2
Figure 2
Structure of compound 1.
Figure 3
Figure 3
Scaffold of compounds 1–13 and the various substituents assessed. Please refer to Table 1 for specific R groups.
Figure 4
Figure 4
Synthesis of compound 13. Reagents and conditions: (a) SnCl2, NaBH3CN, 1-methyl-4-piperidone; (b) Boc2O, dioxane; (c) NaH, DMF, propargyl bromide; (d) EtOAc/HCl; (e) CuI, i-Pr2NH, Pd(PPh3)4, DMSO.
Figure 5
Figure 5
Crystal structure of the p53 Y220C mutant protein bound to compound 10. The p53 Y220C mutant protein is colored gray, with key residues shown as colored stick models (nitrogen atoms colored blue and oxygen atoms highlighted in red). Compound 10 is shown in color, where carbon atoms are cyan, nitrogen atoms are blue, and fluorine atoms are light blue. The dashed red lines indicate hydrogen bonds between the p53 Y220C mutant protein and compound 10. PDB code: 9BR4.
Figure 6
Figure 6
Compound 13 and analogues resulting from the substitution of the piperidine ring.
Figure 7
Figure 7
Fluorine-substituted piperidine analogues 22–31.
See this image and copyright information in PMC

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