RAS GTPase-Cyclophilin A complex (RAS-CypA)

The RAS GTPase-Cyclophilin A complex is a therapeutic target formed through a molecular glue mechanism where a small-molecule inhibitor recruits the endogenous chaperone protein Cyclophilin A (CypA) to bind the active, GTP-bound state of RAS proteins [1][2]. This ternary complex, often referred to as a tricomplex, effectively targets multiple RAS isoforms including KRAS, NRAS, and HRAS, regardless of the specific mutation present [2][3]. By forming this bulky complex, the inhibitor sterically prevents RAS from interacting with its downstream effectors, such as RAF kinases, thereby inhibiting the MAPK/ERK signaling pathway that drives tumor growth [1][4]. This approach is particularly innovative because it targets the active 'ON' state of RAS, which has historically been difficult to inhibit due to the lack of traditional small-molecule binding pockets [3]. Clinically, drugs targeting this complex, such as RMC-6236, are being developed to treat a broad range of RAS-mutated cancers, including pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer [4][5]. The strategy aims to provide a more comprehensive solution to RAS-driven malignancies compared to isoform-specific or mutation-specific inhibitors [2].

Other names

pan-RAS(ON) tricomplexRAS-Cyclophilin A tricomplexRAS-PPIA complexRAS(ON) inhibitor target

Molecular glue-mediated formation of a ternary complex that sterically hinders RAS-effector interactions