Matthew L. Landry, Sushant Malhotra, Maureen H. Beresini, Connie Chan, Emily Chan, Cecile C. de la Cruz, Nicholas Endres, Marie Evangelista, Amy Gustafson, Dennis Hu (23267455), Thomas Hunsaker, Peter Hsu, Yevgeniy Izrayelit, Hank La, Pablo Saenz-Lopez Larrocha, Qihui Lian, Mark Merchant, Jialin Mao, Rana Mroue, Angela Oh, Emile G. Plise, Cheng Shao, Michael Siu, John C. Tran (1471192), Yanguang Wang (1412947), Weiru Wang (640332), BinQing Wei, Susan Wong, Chun-Wan Yen (1559143), Yuhui Zhou (6495551), Hans E. Purkey, Timothy P. Heffron, Laurent Salphati
Mutant KRAS is highly prevalent in human cancer and has been actively pursued as a target for drug discovery. Much progress has been made in drugging KRAS G12C, owing to the ability of inhibitors to covalently target its oncogenic cysteine mutation at codon 12. A number of KRAS G12C inhibitors have advanced to clinical development and are being investigated for the treatment of a variety of solid tumors. Notably, many patients with KRAS G12C-positive non-small cell lung cancer develop brain metastases. Herein, we report the discovery and development of a brain-penetrant inhibitor of KRAS G12C using divarasib as a starting point. Optimization efforts focused on reducing molecular weight and topological polar surface area as well as shielding of hydrogen bond donors. In this manner, active transport by both P-gp and breast cancer resistance protein (BCRP) was attenuated, and high exposure in rodent brain tissue was achieved.