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PMID: 41766690 已发表 · ppublish 英语

Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C.

Journal of medicinal chemistry ·第 69 卷 ·第 5 期 ·2026-03-12

Endres NF, Do S, Mroue R, Terrett JA, Saabye M, Oh A, Hunsaker T, Chan E, Tran JC, Nguyen LK, Lian Q, Ma TP, Garner T, Gerosa L, Beresini M, Boudreau A, Bronner SM, Cyr P, Ishisoko N, Izrayelit Y, Jiang F, Kellar T, La H, Labadie S, Lardy M, Liu L, Liu W, Miller S, Rudolph J, Plise E, Sellers BD, Shao C, Wang W, Wang Y, Wei W, Wong S, Yu C, Yu K, Yuen PW, Zang R, Zhang C, Zhou Y, Zhu X, Quinn JG, Ye X, Kiefer JR, Mao J, Evangelista M, Merchant M, Landry ML, Malhotra S, Purkey HE

摘要

KRAS G12C is one of the most prevalent oncogenic mutations in nonsmall cell lung cancer. Herein we describe the discovery and optimization of divarasib (GDC-6036), an orally available, highly potent, and selective covalent KRAS G12C inhibitor. We demonstrate a significant noncovalent binding component of divarasib that contributes to its potency and rapid kinetics. Divarasib has greater potency and kinetics of alkylation compared with other KRAS G12C inhibitors in vitro and shows robust tumor growth inhibition in multiple KRAS G12C-positive cell lines.

文献信息
期刊
Journal of medicinal chemistry
期刊简称
J Med Chem
ISSN
1520-4804
发表日期
2026-03-12
语言
英语
国家/地区
United States
NLM ID
9716531
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