GTPase KRas (Kirsten rat sarcoma virus oncogene homolog) (KRAS)

GTPase KRas (Kirsten rat sarcoma virus oncogene homolog) is a small GTPase that functions as a critical molecular switch in cellular signaling, alternating between an active GTP-bound state and an inactive GDP-bound state. It plays a central role in the RAS/MAPK and PI3K/AKT pathways, which regulate essential processes such as cell growth, differentiation, and survival (UniProt P01116). Mutations in KRAS, particularly at the G12 position (including G12C, G12D, G12V, and G12R), impair its intrinsic GTPase activity and lead to constitutive activation, driving uncontrolled cell proliferation in various malignancies (PubMed: 33408224). These variants are among the most common oncogenic drivers in pancreatic, colorectal, and non-small cell lung cancers. While KRAS was long considered an undruggable target, the discovery of a cryptic pocket in the G12C variant led to the development of covalent inhibitors like sotorasib and adagrasib (NIH: PMC8311555). Current therapeutic strategies are expanding to target other variants like G12D and G12V using non-covalent inhibitors and RAS-multi inhibitors that target the active state of the protein (PubMed: 37216414).

Other names

KRAS2RASK2KI-RASC-K-RASK-RAS2AK-RAS2BK-RAS4AK-RAS4BKirsten rat sarcoma 2 viral oncogene homologv-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog

Covalent inhibition of the inactive GDP-bound state (specifically for G12C); Non-covalent inhibition of the active or inactive states; Tri-complex inhibition (RAS-multi inhibitors) targeting the active GTP-bound state.