Kirsten rat sarcoma virus oncogene homolog G12X mutant (GTP-bound state) (KRAS G12X (ON))

KRAS G12X mutants in the GTP-bound state represent the active, signaling-competent form of the Kirsten rat sarcoma virus oncogene homolog (UniProt: P01116). Mutations at codon 12, such as G12D, G12V, and G12C, impair the protein's intrinsic GTPase activity and render it insensitive to GTPase-activating proteins (GAPs), resulting in a protein locked in the "ON" state (PubMed: 35408415). This constitutive activation drives downstream oncogenic signaling through the MAPK and PI3K pathways, promoting uncontrolled cell growth and survival in high-prevalence malignancies including pancreatic, colorectal, and non-small cell lung cancers (PubMed: 33473321). While early KRAS inhibitors targeted the inactive GDP-bound state, modern "RAS(ON)" inhibitors are designed to bind the GTP-bound form directly. These inhibitors often utilize a tri-complex mechanism, forming a ternary complex between the drug, the mutant KRAS(GTP), and an intracellular chaperone like Cyclophilin A (PubMed: 37558881). This complex sterically prevents the recruitment of effectors such as RAF, thereby shutting down oncogenic signaling. Targeting the active state is a critical advancement intended to address a wider range of KRAS mutations and overcome resistance associated with state-specific cycling or nucleotide exchange (PubMed: 38233545). This approach offers a potential therapeutic window by selectively targeting the mutant protein's active conformation.

Other names

KRAS G12X (GTP-bound)Active KRAS G12XRAS(ON) G12XK-Ras G12X (active state)

Tri-complex inhibition: The drug forms a ternary complex with the active GTP-bound KRAS mutant and an intracellular chaperone, such as Cyclophilin A, which sterically blocks the interaction between KRAS and its downstream effectors like RAF (PubMed: 37558881).