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
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.