KRAS G12D

Class

Oral small molecule ON/OFF KRAS G12D inhibitor

Pathway

RAS/MAPK signaling

KRAS is a small GTPase that functions as a molecular switch within the RAS/MAPK signaling pathway, cycling between an inactive, GDP-bound state and an active, GTP-bound state that transmits growth signals from cell-surface receptors to the nucleus. The G12D mutation, a substitution at codon 12, impairs the protein's intrinsic and GAP-assisted ability to hydrolyze GTP back to GDP, so the protein accumulates in its active conformation and drives continuous proliferative signaling independent of upstream cues. This mutation is common in pancreatic, colorectal, and other gastrointestinal cancers, and for decades KRAS was considered difficult to drug because its surface lacks deep pockets suitable for small-molecule binding. Newer inhibitors described as 'ON/OFF' are designed to engage KRAS G12D regardless of whether it is bound to GDP or GTP, in contrast to earlier mutant-selective RAS inhibitors that could only trap one nucleotide state. Complementary approaches include molecules that recruit cellular machinery to degrade the mutant protein entirely. Because RAS/MAPK signaling is also required for normal tissue maintenance, therapeutic strategies aim for mutant selectivity to reduce disruption of healthy cell signaling while shutting down the oncogenic drive.