Mutant Rat Sarcoma virus protein (Mutant RAS) (Mutant RAS)

Mutant Rat Sarcoma virus (RAS) proteins, including the KRAS, NRAS, and HRAS isoforms, are small GTPases that function as critical molecular switches in cell signaling pathways regulating growth, differentiation, and survival [1, 4]. In a physiological state, these proteins cycle between an active GTP-bound ON state and an inactive GDP-bound OFF state; however, oncogenic mutations (most commonly at codons 12, 13, or 61) impair GTP hydrolysis, locking the protein in the active configuration and driving autonomous tumor growth [2, 3]. The molecular glue mechanism involving Cyclophilin A (CypA) is a novel therapeutic strategy designed to target the active, GTP-bound form of these mutants, often referred to as RAS(ON) [1, 6]. Drugs employing this mechanism bind to the abundant endogenous chaperone Cyclophilin A to create a binary complex that then associates with the effector-binding face of mutant RAS [2, 5]. This resulting ternary complex (CypA-drug-RAS) sterically prevents RAS from interacting with its downstream signaling effectors, such as RAF kinases, thereby effectively silencing oncogenic signaling [1, 2]. This approach is particularly significant because it allows for the targeting of a wide spectrum of RAS mutations beyond just KRAS G12C, including G12D and G12V, which were previously difficult to inhibit directly [1, 6]. By leveraging the high intracellular concentration of Cyclophilin A, these inhibitors can achieve potent and selective suppression of mutant RAS activity in cancer cells [2, 6].

Other names

KRASNRASHRASp21 RASRAS GTPaseMutant RAS(ON)

Molecular glue mechanism where the drug facilitates the formation of a ternary complex between the intracellular chaperone Cyclophilin A and the active, GTP-bound state of mutant RAS proteins, sterically hindering the binding of downstream effectors like RAF, PI3K, and RALGEF [1, 2, 6].