Discovery of Novel Oral Covalent Inhibitors Targeting Active GTP-Bound KRASG12C with Potent Antitumor Activity.

Current KRASG12C inhibitors mainly target the inactive GDP-bound state, but clinical efficacy is limited, and resistance mechanisms have been identified. We disclose novel covalent inhibitors that selectively target the active GTP-bound KRASG12C. Starting from a high-throughput screen, we identified a keto-indolizine scaffold featuring an aniline-derived acrylamide warhead that covalently binds Cys12 in the switch-II pocket of active KRASG12C. X-ray crystallography revealed key interactions of acrylamide with GMPPCP's γ-phosphate, stabilizing the GTP state. We present medicinal chemistry efforts leading to the discovery of compound 17, which shows favorable oral bioavailability in preclinical species, exhibiting prolonged disruption of the KRAS-cRAF interaction and downstream ERK phosphorylation in vivo. In a KRASG12C-driven pancreatic cancer xenograft model (MIA PaCa-2), orally administered compound 17 achieved complete tumor regression for up to 45 days with good tolerability. This study establishes a novel class of KRASG12C inhibitors targeting the active GTP-bound state, which may have the potential to overcome some resistance mechanisms.