Structure-activity relationship study, target identification, and pharmacological characterization of a small molecular IL-12/23 inhibitor, APY0201.
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.
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Nobuhiko
N
Hayakawa
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Masatsugu
M
Noguchi
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Sen
S
Takeshita
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Agung
A
Eviryanti
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Yukie
Y
Seki
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Hikaru
H
Nishio
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Ryohei
R
Yokoyama
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Misato
M
Noguchi
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Manami
M
Shuto
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Yoichiro
Y
Shima
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Kanna
K
Kuribayashi
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Shunsuke
S
Kageyama
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Hiroyuki
H
Eda
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Manabu
M
Suzuki
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.
Tomohisa
T
Hatta
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.
Shun-Ichiro
S
Iemura
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.
Tohru
T
Natsume
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Itsuya
I
Tanabe
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Ryusuke
R
Nakagawa
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Makoto
M
Shiozaki
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Kuniya
K
Sakurai
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan.
Masataka
M
Shoji
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan. Electronic address: ayatoshi_andou@ajinomoto.com.
Ayatoshi
A
Andou
Research Institute, Ajinomoto Pharmaceuticals Co. Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan. Electronic address: takashia_yamamoto@ajinomoto.com.
Takashi
T
Yamamoto
D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D016753:Interleukin-10 / Q000172:deficiency; D018664:Interleukin-12 / Q000037:antagonists & inhibitors*; D053759:Interleukin-23 / Q000037:antagonists & inhibitors*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C000593705:APY0201; D053759:Interleukin-23; D011720:Pyrazoles; D011743:Pyrimidines; D054852:Small Molecule Libraries; D016753:Interleukin-10; D018664:Interleukin-12
APY0201; IL-12/23; PIKfyve; Target identification