RAS protein (Rat sarcoma virus oncogene protein) and Cyclophilin A (RAS (for RAS protein), CypA (for Cyclophilin A))

RAS proteins are small GTPases that act as molecular switches, regulating cell division, proliferation, and survival; mutations (especially at G12, G13, Q61) can lock RAS in an active state, driving oncogenesis in multiple cancers. Cyclophilin A is the most abundant cyclophilin, functioning as a peptidyl-prolyl isomerase and intracellular chaperone, highly expressed in tumors and implicated in cancer cell invasion, proliferation, and drug resistance. Recent breakthroughs include molecular glue and tri-complex inhibitors that promote binding between Cyclophilin A and mutant RAS, forming a new inhibitory interface that disrupts RAS-effector signaling, leading to tumor regression in clinical models. These strategies represent a new class of cancer therapeutics for previously "undruggable" RAS mutants and highlight the dual targeting of a signal transducer and a chaperone protein[1][3][4][5][6][7][8].

Other names

KRASNRASHRASKirsten rat sarcoma viral oncogene homologNRAS (Neuroblastoma RAS viral oncogene homolog)HRAS (Harvey rat sarcoma viral oncogene homolog)Rat sarcoma viral oncogene proteinCypAPeptidyl-prolyl cis-trans isomerase APPIACyclosporin A-binding protein

Direct covalent inhibition of mutant KRAS at oncogenic sites (G12C, G12D, etc.). Tri-complex formation: molecular glue induces association between mutant RAS and Cyclophilin A, creating a new surface that blocks RAS-effector interactions (e.g., RAS-RAF binding), suppressing downstream signaling. Inhibition of isomerase activity and chaperone function for Cyclophilin A (Cyclosporin A, Sanglifehrin derivatives)