KRAS protein G12D mutant (KRAS(G12D))

KRAS protein G12D mutant (KRAS(G12D)) is a constitutively active mutant form of the small GTPase KRAS, resulting from substitution of glycine (G) at position 12 with aspartic acid (D)[1][4][6]. This mutation impairs the intrinsic and GAP-stimulated GTPase activity of KRAS, locking it in a GTP-bound (active) state. As a central node in the RAS/MAPK pathway, mutant KRAS persistently activates downstream proliferative and survival signaling pathways, irrespective of upstream regulatory input. KRAS(G12D) is one of the most common oncogenic KRAS mutations, especially in pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. Efforts to drug KRAS(G12D) have focused on molecules that bind to a mutant-enlarged switch-II pocket or interact with Asp12, forming the basis of highly specific inhibitors and biologics currently in preclinical and clinical development. Resistance, specificity for the mutant over wild-type, and the need for precise patient selection are key therapeutic challenges[1][3][4][6].

Other names

KRAS G12DKRAS glycine-12-aspartate mutantK-Ras mutant G12DKirsten rat sarcoma viral oncogene homolog G12D mutant

Small molecules and polypeptides: bind to the switch-II pocket or nearby regions, exploiting the structural difference conferred by the G12D mutation to selectively inhibit KRAS(G12D) signaling; often form direct contacts or salt bridges with Asp12[1][6] Intracellular biologics (monobodies): block KRAS(G12D) interaction with effectors (e.g., RAF, PI3K) and inhibit downstream signaling[1]