GTP-bound pan-RAS-Cyclophilin A ternary complex (RAS(ON):CypA)

The GTP-bound pan-RAS-Cyclophilin A ternary complex is a therapeutic target assembly formed by a molecular glue drug, the intracellular chaperone Cyclophilin A (CypA), and the active (GTP-bound) state of RAS proteins [1, 3]. RAS proteins, including KRAS, NRAS, and HRAS, are small GTPases that regulate critical signaling pathways like MAPK/ERK and PI3K/AKT to control cell growth and survival [2]. In many cancers, mutations lock RAS in the active GTP-bound "ON" state, leading to uncontrolled proliferation [2, 4]. This ternary complex approach uses a drug to recruit CypA to the surface of RAS-GTP, creating a steric shield that prevents RAS from interacting with its downstream effector proteins [3]. Unlike traditional covalent inhibitors that target the inactive GDP-bound state of specific mutants like KRAS G12C, this mechanism targets the active state of multiple RAS isoforms (pan-RAS) [1, 4]. This strategy is particularly effective because it addresses the "ON" state, which is the biologically active driver of the disease [3]. Clinical candidates like RMC-6236 utilize this mechanism to treat a wide range of RAS-mutated solid tumors, including pancreatic, lung, and colorectal cancers [1]. The formation of this complex represents a significant advancement in overcoming the "undruggable" nature of RAS by leveraging protein-protein interactions [2, 3].

Other names

RAS(ON) tri-complexCypA-RAS-GTP complexpan-RAS(ON) inhibitor targetCyclophilin A-RAS-GTP ternary complex

Tri-complex inhibition (molecular glue mechanism) where a drug binds to the chaperone Cyclophilin A to form a binary complex that subsequently binds to the effector-binding face of GTP-bound (active) RAS, sterically preventing interaction with downstream effectors like RAF [1, 3].