IL-12 and IL-23 are pro-inflammatory cytokines which induce serious pathological conditions in diverse of inflammatory diseases such as inflammatory bowel disease (IBD), psoriasis and rheumatoid arthritis. The therapeutic potential of IL-12/23 inhibition has been validated in clinical by Ustekinumab which is an approved monoclonal antibody neutralizing IL-12/23.Through the cell-based phenotypic screening and extensive medicinal chemistry campaign, we generated APY0201 as a potent and unique inhibitor for IL-12/23 production from activated macrophages, possessing significant selectivity over other cytokines including TNF-a. As a result of chemical proteomics approach and comprehensive analysis of compound-protein binding using highly sensitive direct nano-flow liquid chromatography/tandem mass spectrometry system, PIKfyve kinase was identified as a biological target of our promising IL-12/23 production inhibitor. APY0201 is a potent, highly selective and ATP-competitive PIKfyve kinase inhibitor, which ameliorated inflammation in experimental model of colitis. We will disclose the SAR, biological evaluations both in vitro and in vivo, strategy of target identification and unique character of this novel drug target, to treat autoimmune and inflammatory diseases.

Target identification of novel anti-inflammatory compound: Orally available small molecule PIKfyve kinase inhibitors by suppressing IL-12/23 production

243rd National Meeting (2012)

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