apy0201 and Colitis

Interleukin-12 (IL-12) and IL-23 are proinflammatory cytokines and therapeutic targets for inflammatory and autoimmune diseases, including inflammatory bowel diseases, psoriasis, rheumatoid arthritis, and multiple sclerosis. We describe the discovery of APY0201, a unique small molecular IL-12/23 production inhibitor, from activated macrophages and monocytes, and demonstrate ameliorated inflammation in an experimental model of colitis. Through a chemical proteomics approach using a highly sensitive direct nanoflow LC-MS/MS system and bait compounds equipped with the FLAG epitope associated regulator of PIKfyve (ArPIKfyve) was detected. Further study identified its associated protein phosphoinositide kinase, FYVE finger-containing (PIKfyve), as the target protein of APY0201, which was characterized as a potent, highly selective, ATP-competitive PIKfyve inhibitor that interrupts the conversion of phosphatidylinositol 3-phosphate (PtdIns3P) to PtdIns(3,5)P2. These results elucidate the function of PIKfyve kinase in the IL-12/23 production pathway and in IL-12/23-driven inflammatory disease pathologies to provide a compelling rationale for targeting PIKfyve kinase in inflammatory and autoimmune diseases.

Topics: Animals; Cell Line; Colitis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Female; Humans; Inflammation; Interleukin-10; Interleukin-12; Interleukin-23; Leukocytes, Mononuclear; Macrophages; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, SCID; Models, Molecular; Molecular Structure; Pyrazoles; Pyrimidines; Small Molecule Libraries; Structure-Activity Relationship