title: Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A.
abstract: Dyrk1A (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A) is a serine/threonine kinase essential for brain development and function, and its excessive activity is considered a pathogenic factor in Down syndrome. The development of potent, selective inhibitors of Dyrk1A would help to elucidate the molecular mechanisms of normal and diseased brains, and may provide a new lead compound for molecular-targeted drug discovery. Here, we report a novel Dyrk1A inhibitor, INDY, a benzothiazole derivative showing a potent ATP-competitive inhibitory effect with IC(50) and K(i) values of 0.24 and 0.18 μM, respectively. X-ray crystallography of the Dyrk1A/INDY complex revealed the binding of INDY in the ATP pocket of the enzyme. INDY effectively reversed the aberrant tau-phosphorylation and rescued the repressed NFAT (nuclear factor of activated T cell) signalling induced by Dyrk1A overexpression. Importantly, proINDY, a prodrug of INDY, effectively recovered Xenopus embryos from head malformation induced by Dyrk1A overexpression, resulting in normally developed embryos and demonstrating the utility of proINDY in vivo.
authors.affiliation: Laboratory of Gene Expression, Graduate School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Nonaka
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Goto
authors.forename: Eriko
authors.initials: E
authors.lastname: Ohnishi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hiramatsu
authors.forename: Isao
authors.initials: I
authors.lastname: Kii
authors.forename: Miyo
authors.initials: M
authors.lastname: Yoshida
authors.forename: Teikichi
authors.initials: T
authors.lastname: Ikura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Onogi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shibuya
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Hosoya
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Ito
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry; D019556:COS Cells; D002522:Chlorocebus aethiops; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D004314:Down Syndrome / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014982:Xenopus laevis; D016875:tau Proteins / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016875:tau Proteins; D000097603:Dyrk Kinases; C005465:benzothiazole