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Bioorg Med Chem ; 22(11): 3021-9, 2014 Jun 01.
Article in English | MEDLINE | ID: mdl-24767819

ABSTRACT

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.


Subject(s)
Interleukin-12/antagonists & inhibitors , Interleukin-23/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Small Molecule Libraries/pharmacology , Animals , Cell Line , Colitis/drug therapy , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Discovery , Female , Humans , Inflammation/drug therapy , Interleukin-10/deficiency , Leukocytes, Mononuclear/drug effects , Macrophages/drug effects , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, SCID , Models, Molecular , Molecular Structure , Pyrazoles/chemistry , Pyrimidines/chemistry , Small Molecule Libraries/chemistry , Structure-Activity Relationship
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