9BR4

Crystal structure of p53 Y220C mutant in complex with PC-9859

This is a non-PDB format compatible entry.

Summary for 9BR4

• Entry DOI: 10.2210/pdb9br4/pdb
• Descriptor: Cellular tumor antigen p53, 2-methyl-2-{5-[(3-{4-[(1-methylpiperidin-4-yl)amino]-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl}prop-2-yn-1-yl)amino]pyridin-2-yl}propanenitrile, ZINC ION, ... (5 entities in total)
• Functional Keywords: p53, ligand, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 50568.77

Authors

Abendroth, J.,Lorimer, D.D.,Vu, B.,Takana, N. (deposition date: 2024-05-10, release date: 2024-12-18, Last modification date: 2025-01-29)

Primary citation

Vu, B.T.,Dominique, R.,Fahr, B.J.,Li, H.H.,Fry, D.C.,Xu, L.,Yang, H.,Puzio-Kuter, A.,Good, A.,Liu, B.,Huang, K.S.,Tanaka, N.,Davis, T.W.,Dumble, M.L.
Discovery of Rezatapopt (PC14586), a First-in-Class, Small-Molecule Reactivator of p53 Y220C Mutant in Development.
Acs Med.Chem.Lett., 16:34-39, 2025

PubMed Abstract: p53 is a potent transcription factor that is crucial in regulating cellular responses to stress. Mutations in the 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 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 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 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 Y220C mutant solid tumors.

PubMed: 39811143
DOI: 10.1021/acsmedchemlett.4c00379

Experimental method

X-RAY DIFFRACTION (1.7 Å)