9BR4

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

これはPDB形式変換不可エントリーです。

9BR4 の概要

• エントリーDOI: 10.2210/pdb9br4/pdb
• 分子名称: 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)
• 機能のキーワード: p53, ligand, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 50568.77

構造登録者

Abendroth, J.,Lorimer, D.D.,Vu, B.,Takana, N. (登録日: 2024-05-10, 公開日: 2024-12-18, 最終更新日: 2025-01-29)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.7 Å)