Oncogenic RAS mutants (GTP-bound) in complex with Cyclophilin A (RAS(ON):CypA tri-complex)

The Oncogenic RAS mutants via CypA-mediated tri-complex refers to a therapeutic target comprising the active, GTP-bound state of mutated RAS proteins (KRAS, NRAS, or HRAS) in a ternary complex with the chaperone protein Cyclophilin A (CypA) and a small-molecule inhibitor [Revolution Medicines, 2023]. RAS mutations are among the most frequent drivers of human malignancy, particularly in pancreatic, colorectal, and lung cancers, where they promote constitutive signaling for cell growth and survival [Nature, 2023]. This target is unique because it utilizes a molecular glue mechanism, where the drug first binds to the abundant intracellular protein CypA [Science, 2023]. The resulting drug-CypA binary complex then recognizes and binds to the active ON state of the RAS mutant, which has historically been difficult to target due to its smooth surface and lack of deep binding pockets [Cancer Discovery, 2024]. By forming this tri-complex, the drug sterically blocks the interaction between RAS and its downstream effectors, such as RAF, effectively shutting down the MAPK/ERK signaling pathway [PubMed: 37558881]. This approach allows for the inhibition of a broad spectrum of RAS mutations, including G12D, G12V, and G13D, which are not addressed by first-generation covalent inhibitors [Revolution Medicines, 2024]. Clinical development of drugs targeting this complex, such as RMC-6236, has shown promising activity across multiple RAS-mutated tumor types [ASCO, 2023]. Therapeutic challenges include maintaining selectivity over wild-type RAS to minimize systemic toxicity and managing side effects like gastrointestinal distress and skin reactions [Journal of Clinical Oncology, 2024].

Other names

RAS(ON) tri-complexTri-complex RAS inhibitorsCypA-mediated RAS complexActive-state RAS molecular glue complexRAS-GTP:Cyclophilin A complex

Molecular glue / Tri-complex formation: The drug binds to the endogenous chaperone protein Cyclophilin A (CypA), and the resulting binary complex then binds to the active, GTP-bound state of oncogenic RAS (RAS-ON). This formation creates a steric shield that prevents RAS from interacting with its downstream effectors, such as RAF, thereby inhibiting oncogenic signaling.