Peptidyl-prolyl cis-trans isomerase A–Kirsten rat sarcoma virus oncogene homolog complex (CypA–KRAS)

The Cyclophilin A–KRAS complex is a therapeutic target formed by a novel class of "tri-complex" molecular glue inhibitors designed to target the active, GTP-bound state of KRAS (RAS-ON) (Schulze et al., Nature 2023; Nichols et al., Cancer Discovery 2022). These inhibitors first bind to the abundant intracellular chaperone Cyclophilin A (PPIA), creating a binary complex that then selectively binds to the KRAS protein (Revolution Medicines, 2024). This interaction forms a stable ternary complex where Cyclophilin A sterically blocks the effector-binding face of KRAS, preventing its interaction with downstream signaling proteins like RAF and PI3K (Schulze et al., Nature 2023). This mechanism is highly effective against various oncogenic KRAS mutations, including G12D, G12V, and G12C, which are prevalent in pancreatic, colorectal, and lung cancers (Revolution Medicines, 2024). By utilizing Cyclophilin A as a "chaperone-shield," these drugs can overcome the historical challenges of targeting the relatively smooth surface of the KRAS protein (Nichols et al., Cancer Discovery 2022; UniProt P62937, P01116). Clinical-stage candidates like RMC-6236 and RMC-6291 demonstrate the potential of this approach to provide potent and selective inhibition of oncogenic RAS signaling while sparing inactive RAS-GDP (Schulze et al., Nature 2023; Revolution Medicines, 2024).

Other names

Cyclophilin A–KRAS complexPPIA–KRASRAS-ON tri-complexCypA–RASCyclophilin A–Kirsten rat sarcoma virus oncogene homolog complex

Molecular glue-induced formation of a tri-complex (CypA-Drug-KRAS) that sterically inhibits KRAS-effector interactions