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

KRAS G12D is a specific oncogenic mutant of the Kirsten rat sarcoma virus oncogene homolog (KRAS), a small GTPase that acts as a molecular switch in cell signaling [1, 11]. Under normal physiological conditions, KRAS cycles between an active GTP-bound state and an inactive GDP-bound state to regulate pathways like MAPK and PI3K/AKT, which control cell growth, survival, and differentiation [1, 14]. The G12D mutation involves the substitution of glycine with aspartic acid at codon 12, which impairs the protein's intrinsic GTPase activity and its response to GTPase-activating proteins (GAPs), effectively locking the protein in a constitutively active state [5, 11]. This persistent signaling drives uncontrolled cell proliferation and is a primary driver in several aggressive malignancies, including over 90% of pancreatic ductal adenocarcinomas and significant portions of colorectal and non-small cell lung cancers [2, 7, 12]. Historically considered undruggable due to its high affinity for GTP and lack of traditional binding pockets, KRAS G12D has recently emerged as a major therapeutic target [3, 5]. Current drug development strategies include non-covalent inhibitors like MRTX1133 that utilize salt bridges, covalent tri-complex inhibitors like RMC-9805 that target the active state, and targeted protein degraders like ASP3082 [3, 4, 5, 6]. Key therapeutic challenges include the potential for on-target toxicity if wild-type KRAS is inhibited and the rapid emergence of resistance through secondary mutations or bypass signaling [2, 5, 13].

Other names

K-Ras G12DKRAS p.G12DKRAS p.Gly12AspKirsten rat sarcoma 2 viral oncogene homolog G12D

KRAS G12D inhibitors function by binding to the switch II pocket of the mutant protein in either its inactive (GDP-bound) or active (GTP-bound) state, thereby disrupting downstream signaling pathways such as MAPK and PI3K/AKT [1, 3, 14]. Non-covalent inhibitors like MRTX1133 often form a salt bridge with the aspartic acid residue at position 12 [4, 5]. Covalent tri-complex inhibitors like RMC-9805 and zoldonrasib target the active 'ON' state of the protein [3, 10]. Targeted protein degraders (PROTACs) like ASP3082 and ASP4396 induce the ubiquitination and subsequent proteasomal degradation of the mutant KRAS G12D protein [2, 6].