Discovery and Optimization of a Potent, Efficacious, and Brain-Penetrant Inhibitor of KRAS G12C

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 <i>divarasib</i> 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.