KRAS G12V

Class

KRAS G12V-selective RAS(ON) inhibitor (tri-complex inhibitor)

Pathway

RAS/MAPK signaling

KRAS is a small signaling protein that acts as a molecular switch, cycling between an inactive, GDP-bound state and an active, GTP-bound state. In its active state it triggers the RAS/MAPK pathway, a signaling cascade that instructs cells to grow and divide. The G12V mutation replaces a glycine with valine at position 12, impairing the protein's ability to switch itself off and locking it predominantly in the active, growth-promoting conformation. This sustained signaling drives uncontrolled proliferation in a range of cancers carrying this mutation. Because G12V lacks the reactive cysteine that some other KRAS mutants (such as G12C) offer as a covalent drug-binding site, inhibitors must instead target the active, GTP-bound form of the protein directly. Tri-complex inhibitors achieve this by simultaneously engaging KRAS and a cellular chaperone protein, forming a three-part assembly that blocks the mutant protein from interacting with its downstream signaling partners. This class is often described as a RAS(ON) inhibitor, distinguishing it from earlier approaches that only worked on the inactive state. The broader rationale is to shut down a persistently active oncogenic driver at its source, rather than downstream in the pathway.