Structure- and Property-based Design of a Macrocyclic pan-KRAS Inhibitor, AMG 410

KRAS is the most frequently mutated oncogene, driving over 20% of human cancers, including pancreatic, colorectal, lung, endometrial, and gastric tumors. Building on insights from the development of sotorasib (covalent KRAS G12C inhibitor), we leveraged structure- and property-based design to identify a new class of reversible, macrocyclic pan-KRAS inhibitors, culminating in the discovery of AMG 410. AMG 410 is orally bioavailable, highly selective over HRAS and NRAS, and has high affinity for both GTP(on)- and GDP(off)-bound states of KRAS. Non-clinical studies of AMG 410 demonstrate robust antitumor activity.  AMG 410 is currently under clinical evaluation in patients harboring KRAS missense mutations or genetic amplification who have progressed on standard-of-care therapy.