Selective inhibition of the kinase DYRK1A by targeting its folding process

• Published in: Nature communications 2016-04, Vol.7 (1), p.11391-14, Article 11391
• Main Authors: Kii, Isao, Sumida, Yuto, Goto, Toshiyasu, Sonamoto, Rie, Okuno, Yukiko, Yoshida, Suguru, Kato-Sumida, Tomoe, Koike, Yuka, Abe, Minako, Nonaka, Yosuke, Ikura, Teikichi, Ito, Nobutoshi, Shibuya, Hiroshi, Hosoya, Takamitsu, Hagiwara, Masatoshi
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/89; 631/45/275; 631/92/458/1733; 631/92/470; 64/114; Amino Acid Sequence; Animals; Biological Assay; Biology; Biomarkers - metabolism; Cantharidin - pharmacology; Dyrk Kinases; Embryo, Nonmammalian; Gene Expression Regulation, Developmental; HEK293 Cells; Humanities and Social Sciences; Humans; Insects; Kinases; Life sciences; Marine Toxins; Medical research; Molecular Sequence Data; multidisciplinary; Neurological disorders; Okadaic Acid - pharmacology; Oxazoles - pharmacology; Phosphorylation; Phosphorylation - drug effects; Plasmids - chemistry; Plasmids - metabolism; Protein Folding - drug effects; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - chemistry; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proteins; Recombinant Proteins; Science; Science (multidisciplinary); Sequence Alignment; Thiazoles - chemistry; Thiazoles - pharmacology; Transfection; Xenopus laevis - embryology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11391

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. Kinase inhibitors are important drugs and usually target the ATP binding pocket of kinases. Here, Kii et al. report a completely new type of kinase inhibitor that specifically targets the protein folding intermediate state, but not the mature form, of the protein kinase DYRK1A.