RAS-RAF signaling axis:Cyclophilin A tri-complex (RAS-CypA tri-complex)

The RAS-RAF signaling axis:Cyclophilin A (CypA) tri-complex is a drug-induced molecular assembly designed to inhibit the oncogenic signaling of RAS GTPases. This approach utilizes a class of small molecules known as RAS(ON) inhibitors, which bind to the active, GTP-bound conformation of RAS proteins (including KRAS, NRAS, and HRAS) and simultaneously recruit the ubiquitous cytosolic protein Cyclophilin A (PPIA) (Schulze et al., 2023, Cancer Discovery). The resulting tri-complex creates a large steric shield over the RAS effector-binding switch regions, effectively preventing the recruitment and activation of downstream signaling proteins, most notably RAF kinases within the MAPK pathway (Nichols et al., 2022, Nature Reviews Drug Discovery). This mechanism is particularly significant because it can target a wide spectrum of RAS mutations, including those that lack the cysteine residue required for first-generation covalent inhibitors (Hallin et al., 2022, Nature). By disrupting the RAS-RAF interaction, these tri-complexes induce potent anti-tumor activity in various cancers, such as non-small cell lung cancer, pancreatic cancer, and colorectal cancer (Revolution Medicines, 2024). The use of Cyclophilin A as a chaperone is a form of molecular glue therapy that exploits the high abundance of CypA in the cytosol to achieve high-affinity binding and effective effector blockade.

Other names

RAS(ON) tri-complexRAS-GTP:Cyclophilin A complexCyclophilin A-recruiting RAS inhibitor complexRAS-effector tri-complex

Molecular glue-mediated tri-complex formation that sterically hinders the interaction between active, GTP-bound RAS and its downstream effectors, such as RAF kinases.