Rat sarcoma virus GTPase (RAS)

RAS GTPases are a family of small monomeric G proteins that act as critical molecular switches in intracellular signaling pathways [1, 2]. They cycle between an active, GTP-bound 'on' state and an inactive, GDP-bound 'off' state, a process regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) [4, 7]. When active, RAS proteins recruit and activate downstream effectors, such as RAF kinases and PI3K, which propagate signals for cell proliferation, differentiation, and survival [3, 6]. Mutations in the three primary human RAS genes—KRAS, HRAS, and NRAS—are found in approximately 30% of all human cancers, making them some of the most significant oncogenic drivers [5, 10]. These mutations typically impair the protein's ability to hydrolyze GTP, locking it in a constitutively active state that drives malignant transformation [1, 14]. While historically considered 'undruggable,' recent advancements have led to the approval of covalent inhibitors targeting specific mutations like KRAS G12C and the development of multi-selective inhibitors that target the active state of various RAS isoforms [5, 12, 13].

Other names

KRASHRASNRASp21Small GTPaseRat sarcoma virus oncogene

Covalent inhibition of KRAS G12C, non-covalent tri-complex inhibition of active RAS(ON), inhibition of farnesylation, and inhibition of membrane localization.