9CT7

Tricomplex of Compound 1, KRAS G12D, and CypA

これはPDB形式変換不可エントリーです。

9CT7 の概要

• エントリーDOI: 10.2210/pdb9ct7/pdb
• 分子名称: Isoform 2B of GTPase KRas, Peptidyl-prolyl cis-trans isomerase A, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (7 entities in total)
• 機能のキーワード: kras, cypa, g12d, gtpase, tri-complex, inhibitor-complex, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 77886.85

構造登録者

Zhang, D.,Bar Ziv, T.,Knox, J.E.,Yano, J.K. (登録日: 2024-07-24, 公開日: 2025-07-23, 最終更新日: 2025-08-06)

主引用文献

Weller, C.,Burnett, G.L.,Jiang, L.,Chakraborty, S.,Zhang, D.,Vita, N.A.,Dilly, J.,Kim, E.,Maldonato, B.,Seamon, K.,Eilerts, D.F.,Milin, A.,Marquez, A.,Spradlin, J.,Helland, C.,Gould, A.,Ziv, T.B.,Dinh, P.,Steele, S.L.,Wang, Z.,Mu, Y.,Chugh, S.,Feng, H.,Hennessey, C.,Wang, J.,Roth, J.,Rees, M.,Ronan, M.,Wolpin, B.M.,Hahn, W.C.,Holderfield, M.,Wang, Z.,Koltun, E.S.,Singh, M.,Gill, A.L.,Smith, J.A.M.,Aguirre, A.J.,Jiang, J.,Knox, J.E.,Wildes, D.
A neomorphic protein interface catalyzes covalent inhibition of RAS G12D aspartic acid in tumors.
Science, 389:eads0239-eads0239, 2025

PubMed Abstract: Mutant RAS proteins are among the most prevalent drivers of human cancer, and the glycine to aspartic acid mutation at codon 12 (G12D) is the most common variant. Mutation-selective covalent inhibitors spare RAS in healthy tissue and enable extended pharmacodynamic effect, but covalent targeting of RAS is hindered by low nucleophilicity and high proteomic abundance of carboxylic acids. We overcame these challenges with compounds that bind cyclophilin A (CYPA) to create a neomorphic protein-protein interface between CYPA and active RAS that enables selective, enzyme-like rate enhancement of the covalent reaction between D12 and electrophilic warheads with exceptionally low intrinsic reactivity. This approach yielded orally bioavailable compounds with marked antitumor activity in multiple preclinical models of KRAS cancers, including the investigational agent zoldonrasib (RMC-9805) currently undergoing clinical evaluation (NCT06040541).

PubMed: 40705880
DOI: 10.1126/science.ads0239

実験手法

X-RAY DIFFRACTION (1.42 Å)