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

Nicholas Endres; Steven Do; Rana Mroue; Jack A. Terrett; Matt Saabye; Angela Oh; Thomas Hunsaker; Emily Chan; John C. Tran (1471192); Lan K. Nguyen; Qihui Lian; Taylur P. Ma (14723765); Thomas P. Garner; Luca Gerosa; Maureen H. Beresini; Aaron Boudreau; Sarah M. Bronner; Patrick Cyr (1566223); Noriko Ishisoko; Yevgeniy Izrayelit; Fan Jiang; Terry Kellar (1503187); Hank La; Sharada S. Labadie; Matthew Lardy; Liling Liu (296450); Wendy Liu (2057074); Sarah Miller; Joachim Rudolph; Emile G. Plise; Benjamin D. Sellers; Cheng Shao; Weiru Wang (640332); Yanguang Wang (1412947); Wentao Wei (2135263); Susan Wong; Christine Yu; Kebing Yu; Po-Wai Yuen (1600636); Richard Zang; Chenghong Zhang (2069491); Yuhui Zhou (6495551); Xiaoyu Zhu; John G. Quinn; Xin Ye; James R. Kiefer; Jialin Mao; Marie Evangelista; Mark Merchant; Matthew L. Landry; Sushant Malhotra; Hans E. Purkey

doi:10.1021/acs.jmedchem.5c02272

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

Journal of Medicinal Chemistry 2026 Open access

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Authors: Nicholas Endres, Steven Do, Rana Mroue, Jack A. Terrett, Matt Saabye, Angela Oh, Thomas Hunsaker, Emily Chan, John C. Tran (1471192), Lan K. Nguyen, Qihui Lian, Taylur P. Ma (14723765)

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Thomas P. Garner, Luca Gerosa, Maureen H. Beresini, Aaron Boudreau, Sarah M. Bronner, Patrick Cyr (1566223), Noriko Ishisoko, Yevgeniy Izrayelit, Fan Jiang, Terry Kellar (1503187), Hank La, Sharada S. Labadie, Matthew Lardy, Liling Liu (296450), Wendy Liu (2057074), Sarah Miller, Joachim Rudolph, Emile G. Plise, Benjamin D. Sellers, Cheng Shao, Weiru Wang (640332), Yanguang Wang (1412947), Wentao Wei (2135263), Susan Wong, Christine Yu, Kebing Yu, Po-Wai Yuen (1600636), Richard Zang, Chenghong Zhang (2069491), Yuhui Zhou (6495551), Xiaoyu Zhu, John G. Quinn, Xin Ye, James R. Kiefer, Jialin Mao, Marie Evangelista, Mark Merchant, Matthew L. Landry, Sushant Malhotra, Hans E. Purkey

DOI: 10.1021/acs.jmedchem.5c02272

Cited by: 3

References: 62

Abstract

High Resolution Image Download MS PowerPoint Slide 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.

Fields of Study & Subjects

Protein Kinase Regulation and GTPase Signaling PI3K/AKT/mTOR signaling in cancer Lung Cancer Treatments and Mutations

Publication details

Journal / source: Journal of Medicinal Chemistry
Publisher: American Chemical Society (ACS)
Volume: 69
Issue: 5
Pages: 5147–5165
Publication date: 2 March 2026
Language: EN

References 62