title: Design and synthesis of a potent inhibitor of class 1 DYRK kinases as a suppressor of adipogenesis.
abstract: Dysregulation of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) has been demonstrated in several pathological conditions, including Alzheimer's disease and cancer progression. It has been recently reported that a gain of function-mutation in the human DYRK1B gene exacerbates metabolic syndrome by enhancing obesity. In the previous study, we developed an inhibitor of DYRK family kinases (INDY) and demonstrated that INDY suppresses the pathological phenotypes induced by overexpression of DYRK1A or DYRK1B in cellular and animal models. In this study, we designed and synthesized a novel inhibitor of DYRK family kinases based on the crystal structure of the DYRK1A/INDY complex by replacing the phenol group of INDY with dibenzofuran to produce a derivative, named BINDY. This compound exhibited potent and selective inhibitory activity toward DYRK family kinases in an in vitro assay. Furthermore, treatment of 3T3-L1 pre-adipocytes with BINDY hampered adipogenesis by suppressing gene expression of the critical transcription factors PPARγ and C/EBPα. This study indicates the possibility of BINDY as a potential drug for metabolic syndrome.
authors.affiliation: Laboratory for Malignancy Control Research, Medical Innovation Center, Graduate School of Medicine, Kyoto University, 53, Shigoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: So
authors.initials: S
authors.lastname: Masaki
authors.affiliation: Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Kii
authors.affiliation: Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Sumida
authors.affiliation: Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Kato-Sumida
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Department of Structural Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Ito
authors.affiliation: Division of Natural Sciences, Graduate School of Integrated Arts and Sciences, University of Tokushima, Tokushima 770-8502, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Sonamoto
authors.affiliation: Laboratory for Malignancy Control Research, Medical Innovation Center, Graduate School of Medicine, Kyoto University, 53, Shigoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kataoka
authors.affiliation: Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Hosoya
authors.affiliation: Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: hagiwara.masatoshi.8c@kyoto-u.ac.jp.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D001572:Benzofurans; D052160:Benzothiazoles; D022763:CCAAT-Enhancer-Binding Protein-alpha; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C000607520:1-(1-ethylbenzo(2,3)benzofuro(4,5-d)thiazol-2(1H)-ylidene)propan-2-one; C023614:dibenzofuran
keywords: Adipogenesis; DYRK1; Dibenzofuran; Docking model; Kinase inhibitor; Structural modification