9AX6

Tricomplex of RMC-6236, KRAS G12D, and CypA

これはPDB形式変換不可エントリーです。

9AX6 の概要

• エントリーDOI: 10.2210/pdb9ax6/pdb
• 分子名称: GTPase KRas, Peptidyl-prolyl cis-trans isomerase A, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (6 entities in total)
• 機能のキーワード: inhibitor, complex, small gtpase, cancer, tricomplex, signaling protein-inhibitor complex, 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: 77751.78

構造登録者

Tomlinson, A.C.A.,Saldajeno-Concar, M.,Knox, J.E.,Yano, J.K. (登録日: 2024-03-05, 公開日: 2024-04-17, 最終更新日: 2024-06-12)

主引用文献

Jiang, J.,Jiang, L.,Maldonato, B.J.,Wang, Y.,Holderfield, M.,Aronchik, I.,Winters, I.P.,Salman, Z.,Blaj, C.,Menard, M.,Brodbeck, J.,Chen, Z.,Wei, X.,Rosen, M.J.,Gindin, Y.,Lee, B.J.,Evans, J.W.,Chang, S.,Wang, Z.,Seamon, K.J.,Parsons, D.,Cregg, J.,Marquez, A.,Tomlinson, A.C.A.,Yano, J.K.,Knox, J.E.,Quintana, E.,Aguirre, A.J.,Arbour, K.C.,Reed, A.,Gustafson, W.C.,Gill, A.L.,Koltun, E.S.,Wildes, D.,Smith, J.A.M.,Wang, Z.,Singh, M.
Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.
Cancer Discov, 14:994-1017, 2024

PubMed Abstract: RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models. Translational PK/efficacy and PK/PD modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, we describe here objective responses in two patients (at 300 mg daily) with advanced KRASG12X lung and pancreatic adenocarcinoma, respectively, demonstrating the initial activity of RMC-6236 in an ongoing phase I/Ib clinical trial (NCT05379985).

PubMed: 38593348
DOI: 10.1158/2159-8290.CD-24-0027

実験手法

X-RAY DIFFRACTION (1.65 Å)