Selective inhibition of the kinase DYRK1A by targeting its folding process

Isao Kii (), Yuto Sumida, Toshiyasu Goto, Rie Sonamoto, Yukiko Okuno, Suguru Yoshida, Tomoe Kato-Sumida, Yuka Koike, Minako Abe, Yosuke Nonaka, Teikichi Ikura, Nobutoshi Ito, Hiroshi Shibuya, Takamitsu Hosoya and Masatoshi Hagiwara ()
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Isao Kii: Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho
Yuto Sumida: Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University
Toshiyasu Goto: Medical Research Institute, Tokyo Medical and Dental University
Rie Sonamoto: Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho
Yukiko Okuno: Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho
Suguru Yoshida: Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University
Tomoe Kato-Sumida: Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University
Yuka Koike: Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho
Minako Abe: Graduate School of Medical and Dental Sciences, Medical Research Institute, Tokyo Medical and Dental University
Yosuke Nonaka: Graduate School of Medical and Dental Sciences, Medical Research Institute, Tokyo Medical and Dental University
Teikichi Ikura: Graduate School of Medical and Dental Sciences, Medical Research Institute, Tokyo Medical and Dental University
Nobutoshi Ito: Graduate School of Medical and Dental Sciences, Medical Research Institute, Tokyo Medical and Dental University
Hiroshi Shibuya: Medical Research Institute, Tokyo Medical and Dental University
Takamitsu Hosoya: Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University
Masatoshi Hagiwara: Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract Autophosphorylation of amino-acid residues is part of the folding process of various protein kinases. Conventional chemical screening of mature kinases has missed inhibitors that selectively interfere with the folding process. Here we report a cell-based assay that evaluates inhibition of a kinase at a transitional state during the folding process and identify a folding intermediate-selective inhibitor of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), which we refer to as FINDY. FINDY suppresses intramolecular autophosphorylation of Ser97 in DYRK1A in cultured cells, leading to its degradation, but does not inhibit substrate phosphorylation catalysed by the mature kinase. FINDY also suppresses Ser97 autophosphorylation of recombinant DYRK1A, suggesting direct inhibition, and shows high selectivity for DYRK1A over other DYRK family members. In addition, FINDY rescues DYRK1A-induced developmental malformations in Xenopus laevis embryos. Our study demonstrates that transitional folding intermediates of protein kinases can be targeted by small molecules, and paves the way for developing novel types of kinase inhibitors.

Date: 2016
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DOI: 10.1038/ncomms11391

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