Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A

Yasushi Ogawa, Yosuke Nonaka, Toshiyasu Goto, Eriko Ohnishi, Toshiyuki Hiramatsu, Isao Kii, Miyo Yoshida, Teikichi Ikura, Hiroshi Onogi, Hiroshi Shibuya, Takamitsu Hosoya, Nobutoshi Ito and Masatoshi Hagiwara ()
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Yasushi Ogawa: Laboratory of Gene Expression, Graduate School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku
Yosuke Nonaka: Laboratory of Gene Expression, Graduate School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku
Toshiyasu Goto: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku
Eriko Ohnishi: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku
Toshiyuki Hiramatsu: Laboratory of Chemical Biology, Graduate School of Biomedical Science, Institute of Biomaterials and Bioengineering, 2-3-10, Kandasurugadai, Chiyoda-ku
Isao Kii: Laboratory of Gene Expression, Graduate School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku
Miyo Yoshida: KinoPharma, 1-5-45, Yushima, Bunkyo-ku
Teikichi Ikura: Graduate School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku
Hiroshi Onogi: Laboratory of Gene Expression, Graduate School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku
Hiroshi Shibuya: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku
Takamitsu Hosoya: Laboratory of Chemical Biology, Graduate School of Biomedical Science, Institute of Biomaterials and Bioengineering, 2-3-10, Kandasurugadai, Chiyoda-ku
Nobutoshi Ito: Graduate School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku
Masatoshi Hagiwara: Laboratory of Gene Expression, Graduate School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku

Nature Communications, 2010, vol. 1, issue 1, 1-9

Abstract: 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 IC50 and Ki 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.

Date: 2010
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DOI: 10.1038/ncomms1090

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