K-Ras(G12C) inhibitor 9 is an irreversible, allosteric inhibitor of the K-Ras(G12C) mutant that causes 100% modification of the protein when used at 10 μM for 24 hours in vitro. K-Ras is a small GTPase that cycles between a GTP-bound active state and a GDP-bound inactive state to turn on downstream Raf kinases to drive cell growth. A G12C mutation in K-Ras blocks GTP hydrolysis, activates K-Ras, and promotes carcinogenesis. Similar K-Ras(G12C) inhibitors significantly reduce GTP affinity relative to GDP, decrease Raf binding, and lower cell viability while increasing apoptosis.
