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

KRAS G12D is a specific missense mutation in the Kirsten rat sarcoma virus oncogene homolog (KRAS) where the glycine residue at position 12 is substituted by aspartic acid (UniProt P01116). This mutation severely impairs the protein's intrinsic GTPase activity and its sensitivity to GTPase-activating proteins (GAPs), effectively locking the molecular switch in a constitutively active, GTP-bound state (PubMed: 33479115). The resulting persistent signaling through downstream pathways, such as MAPK/ERK and PI3K/AKT, drives the hallmarks of cancer, including uncontrolled proliferation and metabolic reprogramming (PubMed: 35115233). KRAS G12D is the most prevalent KRAS mutation in human malignancies, found in approximately 40% of pancreatic ductal adenocarcinomas and significant portions of colorectal and lung cancers (PubMed: 34545166). While historically viewed as undruggable, recent therapeutic advances have produced selective inhibitors like MRTX1133 and ASP3082 that exploit the unique chemistry of the aspartate mutation or the Switch II pocket to inhibit oncogenic signaling (ClinicalTrials.gov: NCT05737706). These targeted agents represent a major shift in the treatment landscape for patients with KRAS-mutant solid tumors.

Other names

KRAS proto-oncogene, GTPaseKirsten rat sarcoma 2 viral oncogene homologp21rasRASK2KRAS4B G12D

Small molecule inhibition (covalent or non-covalent) that targets the Switch II pocket or the mutant aspartate residue to stabilize the inactive GDP-bound state or sterically hinder interactions with downstream effector proteins like RAF.