Rat sarcoma virus oncogene homolog (RAS) mutants in complex with Cyclophilin A (RAS-CypA)

The RAS-CypA interface target involves the pharmacological stabilization of a complex between oncogenic RAS mutants and the intracellular protein Cyclophilin A (CypA) (Kim et al., Nature, 2023). RAS proteins, including KRAS, NRAS, and HRAS, are small GTPases that act as molecular switches in cell signaling; mutations that lock RAS in the active, GTP-bound ON state are primary drivers of approximately 30% of all human cancers (Schulze et al., Cancer Discovery, 2023). This target is addressed by a novel class of tri-complex inhibitors, which act as molecular glues by first binding to CypA and then to the active RAS mutant (Revolution Medicines, 2024). This binding event sterically occludes the RAS effector-binding site, effectively preventing the recruitment of downstream signaling proteins such as RAF, PI3K, and RALGEF (Nichols et al., 2022). By leveraging the abundant endogenous chaperone CypA, these inhibitors can achieve high affinity and selectivity for the active state of RAS, which has historically been difficult to target directly due to the lack of traditional drug-binding pockets. This therapeutic strategy is currently being explored to treat a wide range of RAS-driven malignancies, including pancreatic, colorectal, and lung cancers (Revolution Medicines, 2024).

Other names

RAS-PPIA interfaceRAS(ON) tri-complexCyclophilin A-RAS complexActive RAS-CypA complexRAS-CypA molecular glue target

Molecular glue-induced tri-complex formation that sterically inhibits RAS-effector interactions