Kirsten rat sarcoma viral oncogene homolog (G12D) (KRAS G12D)

The **Kirsten rat sarcoma viral oncogene homolog (G12D)**, abbreviated as **KRAS G12D**, is a mutant form of the KRAS protein where glycine at position 12 is replaced with aspartic acid. KRAS is a small GTPase that functions as a molecular switch in the regulation of cell proliferation and differentiation, cycling between an active GTP-bound and inactive GDP-bound state[3][5]. The G12D mutation impairs GTP hydrolysis due to steric and electrostatic changes at the active site, locking KRAS in its active state and driving persistent signaling through downstream effectors**—notably, the MAPK and PI3K pathways**. This uncontrolled signaling underlies its role as a pivotal oncogene in cancers, particularly **pancreatic, colorectal, and lung malignancies**[2][4][5]. Targeting KRAS G12D has been a major pharmaceutical goal due to its prevalence and significance in human cancers, but direct inhibitors have proven challenging to develop. Recent approaches include development of mutant-selective peptides, small molecules that disrupt mutant KRAS-effector or regulator interactions, and agents that allosterically restore sensitivity to regulatory GTPase-activating proteins[2][6][7]. The mutation is clinically actionable as a **biomarker** for patient stratification, with ongoing trials for mutant-selective inhibitors. Safety concerns revolve around the essential signaling roles of RAS proteins in non-malignant tissues and the development of resistance mechanisms[6].

Other names

KRas(G12D)K-Ras G12D mutantKRAS mutant G12DRas G12D

Inhibition of mutant K-Ras GTP-bound signaling state; Disruption of effector protein binding (e.g., blocking Switch II/effector groove); Enhancement of GTPase activity or stabilization of inactive complex