KRAS G12C

Class

KRAS G12C covalent inhibitor

Pathway

Irreversibly binds mutant KRAS G12C cysteine residue, locking RAS in an inactive GDP-bound state, blocking downstream MAPK signaling

KRAS is a small enzyme, a GTPase, that functions as a molecular switch within cells, cycling between an inactive state bound to GDP and an active state bound to GTP. In this active state it triggers the MAPK signaling cascade, a chain of protein activations that drives cell growth and division. The G12C mutation, a substitution at position 12 that introduces a reactive cysteine amino acid, impairs the cell's normal mechanisms for switching KRAS off, so the protein accumulates in its active, signal-sending form and drives uncontrolled proliferation. KRAS G12C covalent inhibitors exploit this exact mutation: they form an irreversible chemical bond with the mutant cysteine, but only when the protein is transiently in its inactive, GDP-bound conformation, trapping it there and shutting down downstream signaling. Because this cysteine is unique to the mutant protein, these drugs can act on tumor cells while largely sparing normal cells carrying unmutated KRAS, addressing a target once considered biologically inaccessible to small molecules. This mechanism is relevant across solid tumors where the G12C mutation occurs, including certain lung and colorectal cancers, and represents a broader strategy of mutation-specific targeting within the RAS family of oncogenes.