Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C
- J Med Chem. 2026 Mar 12;69(5):5147-5165. doi: 10.1021/acs.jmedchem.5c02272.
- 1. Genentech, Inc., South San Francisco, California 94080, United States.
- 2. Confluence Discovery Technologies, 4340 Duncan Ave., St. Louis, Missouri 63110, United States.
- 3. Wuxi Apptec 288 Fu Te Zhong Lu, Wai Gaio Qiao Free Trade Zone, Shanghai 200131, China.
- 4. Viva Biotech, No.735, Ziping Road, Pudong New Area, Shanghai 201318, China.
- 5. Crinetics Pharmaceuticals Inc, San Diego, California 92121-4718, United States.
- 6. Pharmaron-Beijing Co. Ltd., 6 Taihe Road, BDA, Beijing 100176, China.
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.
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