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

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 KRASG12C inhibitors, such as sotorasib and adagrasib, has fueled intense interest in expanding KRAS-directed therapies to mutations beyond KRASG12C, such as KRASG12D, KRASG12V, and KRASG13D. 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 KRASG12D and KRASG12V tumor xenografts following oral administration. AM-2383 represents an important proof-of-concept that structural insights from prior covalent KRASG12C inhibitors can be leveraged in the design of efficacious and well-tolerated inhibitors of diverse KRAS mutations.