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

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

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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