RAS-Cyclophilin A tri-complex (RAS:CypA) (RAS:CypA)

The RAS-Cyclophilin A (RAS:CypA) tri-complex is a therapeutic target assembly formed by a molecular glue drug, a RAS family small GTPase, and the intracellular chaperone protein Cyclophilin A (PPIA) [1]. In this pharmacological model, a small molecule inhibitor first binds to Cyclophilin A to form a binary complex, which then selectively binds to the active, GTP-bound state of RAS (RAS(ON)) [2]. This formation creates a ternary tri-complex that sterically hinders the interaction between RAS and its downstream effectors, such as RAF kinases, PI3K, and RAL-GDS [3]. By blocking these interactions, the tri-complex effectively shuts down oncogenic signaling pathways like MAPK and PI3K/AKT that drive cell proliferation and survival in cancer [4]. This approach is particularly innovative as it allows for the targeting of various RAS mutations (e.g., G12D, G12V, G13D) and isoforms (KRAS, NRAS, HRAS) that were previously considered undruggable in their active states [5]. Clinical-stage compounds like RMC-6236 and RMC-6291 are currently being evaluated for their ability to stabilize this tri-complex in patients with KRAS-mutant solid tumors [6]. References: [1] Revolution Medicines (2024); [2] Schulze et al., Nature (2023); [3] Nichols et al., Cancer Discovery (2022); [4] Kim et al., J. Med. Chem. (2020); [5] Hallin et al., Nature Medicine (2022); [6] ClinicalTrials.gov (2024).

Other names

RAS(ON) tri-complexKRAS:CypA complexCyclophilin A-RAS complexPPIA-RAS complexRAS-PPIA tri-complex

Tri-complex (molecular glue) inhibition of the active, GTP-bound state of RAS (RAS(ON))