Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C
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 <i>in vitro</i> and shows robust tumor growth inhibition in multiple KRAS G12C-positive cell lines.
Authors
- Kebing Yu
- Richard Zang
- Aaron Boudreau (ORCID: https://orcid.org/0009-0005-1710-7503)
- Hans E. Purkey (ORCID: https://orcid.org/0000-0002-8570-364X)
- John G. Quinn (ORCID: https://orcid.org/0000-0002-4664-6232)
- Marie Evangelista (ORCID: https://orcid.org/0000-0003-4623-1595)
- Matthew Lardy
- Cheng Shao
- Sharada S. Labadie
- Joachim Rudolph (ORCID: https://orcid.org/0000-0002-0806-6106)
- Lan K. Nguyen (ORCID: https://orcid.org/0000-0003-4040-7705)
- Maureen H. Beresini
- Qihui Lian
- James R. Kiefer (ORCID: https://orcid.org/0000-0001-6317-0902)
- Matt Saabye
- Rana Mroue
- Nicholas Endres (ORCID: https://orcid.org/0009-0005-1086-6048)
- Luca Gerosa
- Christine Yu (ORCID: https://orcid.org/0000-0003-0731-7118)
- Sarah M. Bronner (ORCID: https://orcid.org/0000-0003-4370-6727)
- Yevgeniy Izrayelit
- Thomas Hunsaker (ORCID: https://orcid.org/0000-0001-7665-747X)
- Noriko Ishisoko
- Emile G. Plise
- Hank La
- Steven Do
- Thomas P. Garner
- Fan Jiang
- Benjamin D. Sellers (2553409)
- Po-Wai Yuen (1600636)
- Wendy Liu (2057074)
- Weiru Wang (640332)
- Yuhui Zhou (6495551)
- Taylur P. Ma (14723765)
- Chenghong Zhang (2069491)
- Yanguang Wang (1412947)
- Liling Liu (296450)
- Terry Kellar (1503187)
- John C. Tran (1471192)
- Jack A. Terrett (1318581)
- Wentao Wei (2135263)
- Patrick Cyr (1566223)
- Angela Oh
- Emily Chan
- Sarah Miller
- Xin Ye
- Sushant Malhotra
- Xiaoyu Zhu
- Mark Merchant
- Susan Wong
- Jialin Mao
- Matthew L. Landry
Institutions
- WuXi AppTec (China) (CN)
- Pharmaron (United Kingdom) (GB)
- Crinetics Pharmaceuticals (United States) (US)
- Viva Biotech (China) (CN)
- Confluence Life Sciences (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-03-02
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02272
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00