9BFY

Tri-complex of Compound-14, KRAS G12C, and CypA

これはPDB形式変換不可エントリーです。

9BFY の概要

• エントリーDOI: 10.2210/pdb9bfy/pdb
• 分子名称: GTPase KRas, Peptidyl-prolyl cis-trans isomerase A, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (7 entities in total)
• 機能のキーワード: inhibitor, complex, small gtpase, cancer, tricomplex, signaling protein-inhibitor complex, signaling protein, signaling protein/inhibitor
• 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: 77956.80

構造登録者

Tomlinson, A.C.A.,Saldajeno-Concar, M.,Knox, J.E.,Yano, J.K. (登録日: 2024-04-18, 公開日: 2024-06-12, 最終更新日: 2025-04-09)

主引用文献

Cregg, J.,Pota, K.,Tomlinson, A.C.A.,Yano, J.,Marquez, A.,Liu, Y.,Schulze, C.J.,Seamon, K.J.,Holderfield, M.,Wei, X.,Zhuang, Y.,Yang, Y.C.,Jiang, J.,Huang, Y.,Zhao, R.,Ling, Y.,Wang, Z.,Flagella, M.,Wang, Z.,Singh, M.,Knox, J.E.,Nichols, R.,Wildes, D.,Smith, J.A.M.,Koltun, E.S.,Gill, A.L.
Discovery of Elironrasib (RMC-6291), a Potent and Orally Bioavailable, RAS(ON) G12C-Selective, Covalent Tricomplex Inhibitor for the Treatment of Patients with RAS G12C-Addicted Cancers.
J.Med.Chem., 68:6041-6063, 2025

PubMed Abstract: The discovery of elironrasib (RMC-6291) represents a significant breakthrough in targeting the previously deemed undruggable GTP-bound, active KRAS. To target the active state of RAS (RAS(ON)) directly, we have employed an innovative tri-complex inhibitor (TCI) modality involving formation of a complex with an inhibitor, the intracellular chaperone protein CypA, and the target protein KRAS in its GTP-bound form. The resulting tri-complex inhibits oncogenic signaling, inducing tumor regressions across various preclinical models of KRAS mutant human cancers. Here we report structure-guided medicinal chemistry efforts that led to the discovery of elironrasib, a potent, orally bioavailable, RAS(ON) G12C-selective, covalent, tri-complex inhibitor. The investigational agent elironrasib is currently undergoing phase 1 clinical trials (NCT05462717, NCT06128551, NCT06162221), with preliminary data indicating clinical activity in patients who had progressed on first-generation inactive state-selective KRAS inhibitors.

PubMed: 39993169
DOI: 10.1021/acs.jmedchem.4c02313

実験手法

X-RAY DIFFRACTION (1.26 Å)