GTPase KRas (G12D mutant) (KRAS G12D)

KRAS G12D is a specific mutant form of the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein, characterized by the substitution of glycine with aspartic acid at position 12. This mutation is a predominant driver in several lethal malignancies, including over 90% of pancreatic ductal adenocarcinomas and significant portions of colorectal and lung cancers [1, 2]. The G12D substitution sterically and chemically hinders the hydrolysis of GTP to GDP, effectively locking the protein in a constitutively active "ON" conformation that promotes continuous downstream signaling through the MAPK and PI3K pathways [3]. Historically considered "undruggable" due to the lack of a deep binding pocket and the absence of a reactive cysteine (unlike the G12C mutant), recent breakthroughs have yielded non-covalent inhibitors and degraders [4]. These therapeutic strategies focus on binding to specific pockets in either the active or inactive conformations to disrupt effector engagement or induce protein turnover [5]. Targeting KRAS G12D represents a major frontier in precision oncology, aiming to provide specific treatment options for patients harboring this common oncogenic driver [6].

Other names

Kirsten rat sarcoma virus oncogene homolog G12DKRAS proto-oncogene, GTPase G12Dp21 Ras G12DKRAS p.Gly12Asp

Non-covalent inhibition of the active (GTP-bound) or inactive (GDP-bound) state of the KRAS G12D mutant, or targeted protein degradation.