Abstract ND11: Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers

Mutations in KRAS are the most common oncogenic driver mutations in human cancers. The KRAS G12C mutation is one of the most prevalent KRAS mutations, present in approximately 12% of non-small cell lung cancer, 4% of colorectal cancer, and up to 4% of other cancer types. The recent discovery and development of covalent KRAS G12C inhibitors provides an opportunity to inhibit what has historically been considered to be an “undruggable” target. GDC-6036 is an orally bioavailable, highly potent and selective KRAS G12C inhibitor, with a median IC50 in the sub-nanomolar range and greater than 18,000-fold selectivity for G12C versus non-G12C cell lines. GDC-6036 demonstrates greater potency and selectivity compared with other KRAS G12C inhibitors in vitro, and complete tumor growth inhibition in multiple KRAS G12C-positive cell lines and in xenograft mouse models. We will highlight the research program that led to the discovery and optimization of GDC-6036, which is currently in clinical development. Citation Format: Hans Purkey. Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND11.