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Nat Commun
2010 Oct 05;1:86. doi: 10.1038/ncomms1090.
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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.
???displayArticle.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.
Figure 5 | Whole-embryo xDyrk1A overexpression assay. (a) In vivo rescue of xDyrk1A overexpression-induced deformity. X. laevis embryos were treated with vehicle alone, TG009 (2.5µM) or proINDY (2.5µM). The embryos were injected with 500pg of -globin, xDyrk1A or kinase-inactive xDyrk1A mRNA (xDyrk-K180R) at the eight-cell stage and incubated until they reached stage 40/41. Arrows, eye deformity; arrowheads, head deformity. (b) Rescue rate of embryo deformity. X. laevis embryos were treated with either proINDY (2.5µM) or vehicle alone and injected with 250pg or 500pg of xDyrk1A mRNA.
Uninjected embryos were used as controls. The percentages of normal embryos, embryos with mild deformity and embryos with severe deformity in
each experimental group are depicted in green, yellow and orange, respectively. The embryos were categorized into normal, mild deformity and severe
deformity groups according to the degree of eye, head and trunk deformity, as illustrated in Supplementary Figure S6. The mean percentage from two
independent experiments and the range for each group are shown. The numbers of embryos used were as follows: for vehicle alone and uninjected: 28 and
37 for the first and second experiments, respectively; vehicle alone and 250pg mRNA: 35 and 29; vehicle alone and 500pg mRNA: 41 and 27; proINDY
and uninjected: 39 and 35; proINDY and 250pg mRNA: 23 and 44; and proINDY and 500pg mRNA: 34 and 29. Error bars indicate the range. (c) Reversal
of downregulation of differential neural markers. X. laevis embryos treated with proINDY (2.5µM) or vehicle alone were injected with xDyrk1A mRNA
(500pg) and grew until stage 17. Expression of depicted differentiation markers was analysed by RT–PCR. xOdc is an internal control. Lanes: −RT, negative control without reverse transcriptase; +RT, uninjected and non-treated.
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