DYRK1A resides within the obligate trisomic region of human chromosome 21 and the extra copy of the DYRK1A gene in people with DS causes a 1.5-fold increased expression of the dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) protein 8.
The physiological importance of DYRK1A has been suggested by its proposed relationship with various symptoms of Down syndrome (DS) 5, 6, 7. Innovative ideas are therefore necessary in drug discovery to obtain a highly selective inhibitor of the target kinase.ĭYRK1A, dual-specificity tyrosine-phosphorylation-regulated kinase 1A, is a mammalian orthologue of Drosophila minibrain and is essential for brain development 4. Kinase inhibitors that target ATP-binding pockets sometimes cause adverse side effects by suppressing unintended kinases, because the sequence and structure of the pockets are well-conserved 3. The protein kinase family represents an attractive target for drug development 1, 2. 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.ĭysregulation of protein kinase activity has been implicated in pathological conditions, such as neurological disorders and tumorigenesis. In addition, FINDY rescues DYRK1A-induced developmental malformations in Xenopus laevis embryos. FINDY also suppresses Ser97 autophosphorylation of recombinant DYRK1A, suggesting direct inhibition, and shows high selectivity for DYRK1A over other DYRK family members. 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. 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. Conventional chemical screening of mature kinases has missed inhibitors that selectively interfere with the folding process. Autophosphorylation of amino-acid residues is part of the folding process of various protein kinases.
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