Abstract IA20: Unlocked groove—developing covalent inhibitors of KRASG12C

Abstract KRAS is one of the most frequently mutated oncogenes in human cancer, with KRASp.G12D, p.G12V, and p.G12C constituting the major mutational subtypes across lung, colon, and pancreatic cancers. Despite over three decades of research, indirect approaches targeting KRAS mutant cancers have largely failed to show clinical benefit, and direct approaches have been limited by the apparent “undruggable” nature of KRAS. Recently, remarkable progress has been reported for targeting KRASG12C with small molecules that bind to the shallow, highly flexible P2 pocket of KRAS and form covalent adducts with the adjacent mutant cysteine. This class of inhibitors has demonstrated robust blockade of KRAS signaling and cell viability with substantial selectivity for KRASp.G12C tumors. Clinical validation of this approach is eagerly awaited. We have used iterative covalent library design and screening to develop unique inhibitors of KRASG12C. In one series, co-crystal structures of improved hit molecules revealed that side-chain motion exposed an undescribed shallow groove that was occupied by ligand atoms. This series was optimized to generate inhibitors with promising cellular activities (cellular IC50 ~100-200 nM and selectivity >200-fold vs. non-G12C lines). To further enhance potency, selectivity, and drug-like properties, scaffold hopping was employed. After extensive optimization, potent and selective inhibitors were identified that potently suppressed KRAS-MAPK signaling (cellular phospho-ERK IC50 ~30 nM) and impaired cell viability (IC50 ~2 nM). In mouse xenograft tumor models, these inhibitors induce tumor regressions when dosed orally, once daily at a dose of 30 mg/kg. The results obtained with these inhibitors have critically informed our efforts to develop KRASG12C inhibitors suitable for clinical testing. Citation Format: J. Russell Lipford, Victor Cee, Brian Lanman, Anne Saiki, Karen Rex, Laurie Volak, Roman Shimanovich, Beth Hinkle. Unlocked groove—developing covalent inhibitors of KRASG12C [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA20.