GTPase KRAS G12D mutant (KRAS G12D (also known as K-Ras(G12D)))

KRAS G12D is a mutant form of the KRAS protein, a small GTPase and member of the Ras family, in which glycine at position 12 is replaced by aspartate[1][2]. KRAS acts as a molecular switch controlling multiple signal transduction pathways that regulate cell proliferation, differentiation, and survival; mutation at codon 12, such as G12D, disrupts GTP hydrolysis and locks the protein in its constitutively active GTP-bound state, resulting in persistent activation of downstream oncogenic pathways such as the MAPK/ERK cascade[1][2][3][4]. The G12D mutation is one of the most common activating mutations found in cancers, especially pancreatic, colorectal, and lung cancers, and is associated with poor prognosis[2][3]. While KRAS G12D has historically been considered "undruggable," recent advances have identified peptides (KRpep-2d, KD2) and small molecules (MRTX1133) that exploit a druggable pocket near switch II (S-II) with promising specificity for the mutant protein[2][3][4]. The mutant has become a major focus of drug discovery and biomarker-driven oncology[2][3][4].

Other names

KRAS G12DK-Ras G12D mutantKRAS glycine 12 to aspartate mutantK-Ras(G12D)KRAS p.G12D

Direct covalent/allosteric inhibition of the switch-II pocket (S-II) on KRAS G12D Inhibition of protein–protein interactions (e.g., blockade of guanine nucleotide exchange factor binding) Selective binding to GTP-bound (active) state to lock the protein in an inactive conformation