Rat sarcoma viral oncogene homolog (RAS) (RAS)

The Rat sarcoma viral oncogene homolog (RAS) proteins are a family of small GTPases, including the KRAS, HRAS, and NRAS isoforms, that function as critical binary molecular switches in cellular signaling pathways (Source: UniProt P01116, P01112). They cycle between an inactive GDP-bound state and an active GTP-bound state to regulate downstream effectors like RAF-MEK-ERK and PI3K-AKT, which control cell growth, differentiation, and survival (Source: NIH/NCI). Mutations in RAS genes are among the most frequent drivers of human cancer, occurring in approximately 30% of all tumors, with particularly high prevalence in pancreatic, colorectal, and lung cancers (Source: PubMed PMC4355019). Historically considered "undruggable" due to their high affinity for GTP and lack of traditional small-molecule binding pockets, recent therapeutic advances have successfully targeted specific mutant forms (Source: StatPearls). For example, covalent inhibitors such as sotorasib and adagrasib have been developed to bind the switch II pocket of the KRAS G12C mutant, locking it in the inactive state (Source: PubChem). Despite these successes, therapeutic challenges remain, including the development of acquired resistance through secondary mutations and the need for effective inhibitors against other common variants like G12D and G12V (Source: PubMed PMC8353830).

Other names

RASp21Transforming protein p21GTPase RASKirsten rat sarcoma viral oncogene homologHarvey rat sarcoma viral oncogene homologNeuroblastoma RAS viral oncogene homolog

Covalent inhibition of the switch II pocket in the inactive GDP-bound state; inhibition of farnesyltransferase to prevent membrane localization; inhibition of downstream effector interactions.