For example, the transitional intermediate of Drosophila DYRK2 was inhibited by Purvalanol A, but not by 4,5,6,7-tetrabromo-1H-benzotriazole (TBB), whereas the mature kinase was inhibited by both 18. Interestingly, the intermediate showed different sensitivity to chemical inhibitors from the mature kinase. postulated the existence of a transitional intermediate of these kinases that has biochemical properties distinct from the mature state 18, 19. INDY also inhibits other DYRK family members as well as Cdc2-like kinases 16.ĭYRKs and glycogen synthase kinase 3β (GSK3β) autophosphorylate their own tyrosine residue in their transitional state and phosphorylate serine or threonine residues on their substrates after maturation 17, 18, 19, 20, 21. To repress the excessive activity of DYRK1A, we had previously developed a synthetic small molecule, INDY, which potently suppresses the kinase activity of DYRK1A. In addition, inhibition of DYRK1A increases pancreatic β-cell proliferation, suggesting therapeutic promise for diabetes therapy 14, 15. The hypothesis that the elevated activity of DYRK1A contributes to these neurological disorders has stimulated an interest in DYRK1A as a potential target for therapeutic drugs 4, 12, 13. The excessive DYRK1A activity is not only pivotal in causing the characteristic facial features 9, 10 and congenital heart defects 9 of DS, but is also associated with early-onset of Alzheimer's disease 11, 12.
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. Check the qualifications to see if you may be eligible to participate.Autophosphorylation of amino-acid residues is part of the folding process of various protein kinases. People from diverse and underrepresented groups, such as those who are Asian, Black/African American, Hispanic/Latino, Native American, and/or Pacific IslanderĮach study has specific requirements for participants, called inclusion and exclusion criteria.People with Down syndrome, who are at higher risk for Alzheimer’s disease.People who are identified as at-risk, given their family history, genetic makeup, or biomarkers, which are measures that could signal very early stages of disease.People diagnosed with Alzheimer’s or a related dementia, such as Lewy body dementia, vascular dementia, or frontotemporal dementia.People who are healthy, without symptoms of dementia.But that’s not true! To produce meaningful results, Alzheimer’s and related dementias researchers need a variety of volunteers, including: Nearly everyone! When people think of clinical research for Alzheimer’s and related dementias, they may think that only people with dementia can participate.