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

KRAS G12D is a mutant isoform of the Kirsten rat sarcoma viral oncogene homolog, characterized by a substitution of glycine with aspartic acid at codon 12. This mutation impairs the intrinsic GTPase activity and GAP-mediated hydrolysis, locking the protein in a constitutively active, GTP-bound (ON) state that drives uncontrolled cell proliferation and survival through the MAPK and PI3K pathways (Schulze et al., Nature 2023). The CypA-mediated tri-complex approach is an innovative pharmacological strategy that utilizes a small molecule to act as a molecular glue between the KRAS G12D protein and the abundant intracellular chaperone protein Cyclophilin A (CypA). By forming this stable tri-complex, the drug sterically occludes the effector-binding face of KRAS, preventing its interaction with downstream signaling proteins like RAF (Nichols et al., Cancer Discovery 2022). This approach is highly specific to the mutant protein and allows for the targeting of the active state of KRAS, which has historically been a challenge in drug discovery. KRAS G12D is a predominant driver in several lethal malignancies, including over 90% of pancreatic cancers and significant portions of colorectal and lung adenocarcinomas (Revolution Medicines, 2024).

Other names

KRAS proto-oncogene GTPase G12Dp21 Ras G12DKRAS G12D(ON)GTP-bound KRAS G12D

Tri-complex formation (molecular glue) where a small molecule bridges KRAS G12D and Cyclophilin A (CypA) to sterically inhibit effector binding.