Definition

An orally bioavailable, covalent inhibitor of both the active, guanosine triphosphate (GTP)-bound form and the inactive, guanosine diphosphate (GDP)-bound form of the oncogenic KRAS substitution mutation G12C, with potential antineoplastic activity. Upon oral administration, KRAS G12C inhibitor FMC-376 targets and covalently binds to cysteine 12 within the switch II pocket in both the GTP-bound (ON) and GDP-bound (OFF) state conformations of KRAS G12C. This modifies and inhibits both the GTP-bound (active) and GDP-bound (inactive) forms of KRAS G12C and prevents KRAS G12C(ON)-mediated signaling, which may inhibit tumor cell proliferation. KRAS, a member of the RAS family of oncogenes, serves an important role in cell signaling, division and differentiation. Mutations of KRAS may induce constitutive signal transduction leading to tumor cell growth, proliferation, invasion, and metastasis. GTP-bound KRAS G12C is upregulated in tumor cells that are resistant to many OFF state KRAS G12C inhibitors.