Expanding Addressable KRAS Mutations through the Structure- and Property-Based Design of Dual-State (GDP/GTP), Reversible Pan-KRAS Inhibitors

High Resolution Image Download MS PowerPoint Slide Therapeutically targeting mutant KRAS represents a clinically validated approach for the treatment of solid tumors, including lung, colon, and pancreatic cancers. The approval of covalent KRAS G12C inhibitors, such as sotorasib and adagrasib, has fueled intense interest in expanding KRAS-directed therapies to mutations beyond KRAS G12C, such as KRAS G12D, KRAS G12V, and KRAS G13D . Here, we describe the structure- and property-based design of reversible inhibitors of diverse oncogenic mutants of KRAS, leading to AM-2383, a pan-KRAS inhibitor that blocks signaling via both the GDP(off)- and GTP(on)-bound states of KRAS, while sparing the closely related RAS isoforms HRAS and NRAS. AM-2383 disrupts signaling downstream of KRAS, potently suppressing the growth of KRAS G12D and KRAS G12V tumor xenografts following oral administration. AM-2383 represents an important proof-of-concept that structural insights from prior covalent KRAS G12C inhibitors can be leveraged in the design of efficacious and well-tolerated inhibitors of diverse KRAS mutations.