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

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.
Nicholas F Endres 1 Steven Do 1 Rana Mroue 1 Jack A Terrett 1 Matt Saabye 2 Angela Oh 1 Thomas Hunsaker 1 Emily Chan 1 John C Tran 1 Lan K Nguyen 1 Qihui Lian 3 Taylur P Ma 1 Thomas Garner 1 Luca Gerosa 1 Maureen Beresini 1 Aaron Boudreau 1 Sarah M Bronner 1 Patrick Cyr 1 Noriko Ishisoko 1 Yevgeniy Izrayelit 1 Fan Jiang 4 Terry Kellar 5 Hank La 1 Sharada Labadie 1 Matthew Lardy 1 Liling Liu 1 Wendy Liu 1 Sarah Miller 1 Joachim Rudolph 1 Emile Plise 1 Benjamin D Sellers 1 Cheng Shao 6 Weiru Wang 1 Yanguang Wang 6 Wentao Wei 4 Susan Wong 1 Christine Yu 1 Kebing Yu 1 Po-Wai Yuen 6 Richard Zang 1 Chenghong Zhang 1 Yuhui Zhou 3 Xiaoyu Zhu 3 John G Quinn 1 Xin Ye 1 James R Kiefer 1 Jialin Mao 1 Marie Evangelista 1 Mark Merchant 1 Matthew L Landry 1 Sushant Malhotra 1 Hans E Purkey 1
Affiliations

Affiliations

  • 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.
Abstract

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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