GTPase KRAS G12C mutant (KRAS G12C)

GTPase KRAS G12C mutant is a specific mutant form of the KRAS protein, where glycine at position 12 is substituted by cysteine. KRAS is a small GTPase that alternates between an inactive GDP-bound state and an active GTP-bound state, acting as a molecular switch in signal transduction pathways controlling cell proliferation and survival[2][4]. The G12C mutation blocks the protein's ability to interact productively with GTPase-activating proteins (GAPs), which normally increase KRAS's intrinsic GTPase activity and thus favor inactivation. Instead, the G12C mutant persistently signals to downstream oncogenic pathways, driving malignant transformation, especially in non–small cell lung cancer and other solid tumors[2][3]. Recently, drugs have been developed that exploit a unique, druggable pocket (the switch-II pocket) exposed by the G12C mutation; these drugs bind covalently to cysteine-12 and lock the protein in the inactive state, providing the first targeted therapies for KRAS G12C-driven cancers[2][3].

Other names

KRAS(G12C)KRAS cysteine-12 mutantKirsten rat sarcoma viral oncogene homolog G12C mutant

Covalent inhibition (targeting cysteine-12 within mutant KRAS) Allosteric inhibition (locking KRAS in inactive GDP-bound form) Competitive inhibition for GTP binding