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

Nat Commun. 2010 Oct 5;1:86. doi: 10.1038/ncomms1090.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzothiazoles / chemistry
  • COS Cells
  • Chlorocebus aethiops
  • Chromatography, High Pressure Liquid
  • Crystallography, X-Ray
  • Down Syndrome / enzymology*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • HEK293 Cells
  • Humans
  • Inhibitory Concentration 50
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Xenopus laevis
  • tau Proteins / metabolism

Substances

  • Benzothiazoles
  • Enzyme Inhibitors
  • tau Proteins
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • benzothiazole