Structure-activity relationship study, target identification, and pharmacological characterization of a small molecular IL-12/23 inhibitor, APY0201

  • Bioorg Med Chem. 2014 Jun 1;22(11):3021-9. doi: 10.1016/j.bmc.2014.03.036.
Nobuhiko Hayakawa  1 ,  Masatsugu Noguchi  1 ,  Sen Takeshita  1 ,  Agung Eviryanti  1 ,  Yukie Seki  1 ,  Hikaru Nishio  1 ,  Ryohei Yokoyama  1 ,  Misato Noguchi  1 ,  Manami Shuto  1 ,  Yoichiro Shima  1 ,  Kanna Kuribayashi  1 ,  Shunsuke Kageyama  1 ,  Hiroyuki Eda  1 ,  Manabu Suzuki  1 ,  Tomohisa Hatta  2 ,  Shun-Ichiro Iemura  2 ,  Tohru Natsume  2 ,  Itsuya Tanabe  1 ,  Ryusuke Nakagawa  1 ,  Makoto Shiozaki  1 ,  Kuniya Sakurai  1 ,  Masataka Shoji  1 ,  Ayatoshi Andou  3 ,  Takashi Yamamoto  4
Affiliations
  • 1. Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
  • 2. Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
  • 3. Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan. Electronic address: [email protected].
  • 4. Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan. Electronic address: [email protected].
PMID: 24767819 DOI: 10.1016/j.bmc.2014.03.036
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.

Keywords
APY0201; IL-12/23; PIKfyve; Target identification.
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