KRAS proto-oncogene, GTPase G12D (mutant) (KRAS G12D)

The KRAS proto-oncogene, GTPase G12D (mutant) is an oncogenic variant of the small GTPase KRAS protein, encoded by the KRAS gene, featuring a glycine-to-aspartic acid substitution at codon 12 (G12D). This mutation impairs GTP hydrolysis by sterically hindering GTPase-activating proteins (GAPs), locking KRAS in a constitutively active GTP-bound state that drives persistent downstream signaling through RAF/MEK/ERK MAPK and PI3K pathways, promoting uncontrolled cell proliferation, survival, and tumorigenesis. KRAS G12D is the most prevalent KRAS mutation in pancreatic ductal adenocarcinoma (PDAC, ~45% of cases), colorectal cancer (~12%), and other solid tumors, initiating and maintaining cancer progression while modulating the tumor microenvironment to suppress immune responses like PD-L1 expression. Targeting KRAS G12D has been challenging due to the absence of a nucleophilic cysteine (present in G12C), but recent advances include non-covalent small molecules like MRTX1133 that bind the switch II pocket, forming salt bridges with Asp12 to block effector binding and nucleotide exchange, as well as peptides (e.g., KRpep-2d), monobodies, and PROTACs in preclinical/clinical stages. Emerging therapies also leverage T-cell engineering recognizing G12D neoantigens in specific HLA contexts, showing tumor regression in case reports for metastatic PDAC. Despite progress, selectivity over wild-type KRAS and potency in GTP-bound forms remain key hurdles for clinical translation.

Other names

K-Ras G12DKi-Ras G12Dc-K-ras G12DRASK G12D

Inhibition of nucleotide exchange (prevents GDP/GTP cycling), Allosteric blockade of switch II pocket (inhibits RAF/MEK/ERK and PI3K signaling), Covalent or non-covalent binding to Asp12 in switch II pocket, Suppression of GEF (SOS1) interaction, Blockade of effector (RAF1) binding, Interference with dimerization via α4-α5 interface