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XB-ART-42235
Nat Commun October 5, 2010; 1 86.
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Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A.

Ogawa Y , Nonaka Y , Goto T , Ohnishi E , Hiramatsu T , Kii I , Yoshida M , Ikura T , Onogi H , Shibuya H , Hosoya T , Ito N , Hagiwara M .


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.

PubMed ID: 20981014
Article link: Nat Commun


Species referenced: Xenopus laevis
Genes referenced: dyrk1a dyrk1a.2 mapt nfatc2
GO keywords: brain development [+]

Disease Ontology terms: autosomal dominant non-syndromic intellectual disability 7
OMIMs: INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 7; MRD7

Article Images: [+] show captions
References [+] :
Ahn, DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects. 2006, Pubmed