IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v1y2010i1d10.1038_ncomms1090.html
   My bibliography  Save this article

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

Author

Listed:
  • Yasushi Ogawa

    (Laboratory of Gene Expression, Graduate School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku
    Present address: Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.)

  • Yosuke Nonaka

    (Laboratory of Gene Expression, Graduate School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku
    KinoPharma, 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
    KinoPharma, 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
    Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku)

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.

Suggested Citation

  • Yasushi Ogawa & Yosuke Nonaka & Toshiyasu Goto & Eriko Ohnishi & Toshiyuki Hiramatsu & Isao Kii & Miyo Yoshida & Teikichi Ikura & Hiroshi Onogi & Hiroshi Shibuya & Takamitsu Hosoya & Nobutoshi Ito & M, 2010. "Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A," Nature Communications, Nature, vol. 1(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:1:y:2010:i:1:d:10.1038_ncomms1090
    DOI: 10.1038/ncomms1090
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms1090
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms1090?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Sasha L. Fulton & Wendy Wenderski & Ashley E. Lepack & Andrew L. Eagle & Tomas Fanutza & Ryan M. Bastle & Aarthi Ramakrishnan & Emma C. Hays & Arianna Neal & Jaroslav Bendl & Lorna A. Farrelly & Amni , 2022. "Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Jessie MacAlpine & Martin Daniel-Ivad & Zhongle Liu & Junko Yano & Nicole M. Revie & Robert T. Todd & Peter J. Stogios & Hiram Sanchez & Teresa R. O’Meara & Thomas A. Tompkins & Alexei Savchenko & Ann, 2021. "A small molecule produced by Lactobacillus species blocks Candida albicans filamentation by inhibiting a DYRK1-family kinase," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:1:y:2010:i:1:d:10.1038_ncomms1090. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.