ArticleScientific reports2015
Identification of a DYRK1A Inhibitor that Induces Degradation of the Target Kinase using Co-chaperone CDC37 fused with Luciferase nanoKAZ.
Article in Scientific reports, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 38 citations in OpenAlex.
- Elevated DYRK1A in Primary Tauopathies and Therapeutic Targeting with the Brain-Penetrant Inhibitor DYR533.Research square · 2026Article
- Integrative Insights Into DYRK1A From Molecular Function to Therapeutic Advancement.Chemical biology & drug design · 2026Review
- DYRK1A promotes viral entry of highly pathogenic human coronaviruses in a kinase-independent manner.PLoS biology · 2023Article
- Review
- Review
- Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia.Nature communications · 2021Article
- Druggable Transient Pockets in Protein Kinases.Molecules (Basel, Switzerland) · 2021Review
- The structure-function relationship of oncogenic LMTK3.Science advances · 2020Article
- Proline Hydroxylation Primes Protein Kinases for Autophosphorylation and Activation.Molecular cell · 2020Article
- A novel de novo heterozygous DYRK1A mutation causes complete loss of DYRK1A function and developmental delay.Scientific reports · 2020Article
- Chronic Dyrk1 Inhibition Delays the Onset of AD-Like Pathology in 3xTg-AD Mice.Molecular neurobiology · 2019Article
- Mutations in the sonic hedgehog pathway cause macrocephaly-associated conditions due to crosstalk to the PI3K/AKT/mTOR pathway.American journal of medical genetics. Part A · 2019Article
- Therapeutic Potential of the Hsp90/Cdc37 Interaction in Neurodegenerative Diseases.Frontiers in neuroscience · 2019Review
- Mutational analysis of two residues in the DYRK homology box of the protein kinase DYRK1A.BMC research notes · 2018Article
- ATR Is a Therapeutic Target in Synovial Sarcoma.Cancer research · 2017Article
- DYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain.Scientific reports · 2017Article
- Selective inhibition of the kinase DYRK1A by targeting its folding process.Nature communications · 2016Article
- DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome.Frontiers in behavioral neuroscience · 2016Review
- Emerging roles of DYRK2 in cancer.The Journal of biological chemistryReview
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The protein kinase family includes attractive targets for drug development. Methods for screening of kinase inhibitors remain largely limited to in vitro catalytic assays. It has been shown that ATP-competitive inhibitors antagonize interaction between the target kinase and kinase-specific co-chaperone CDC37 in living cells. Here we show a cell-based method to screen kinase inhibitors using fusion protein of CDC37 with a mutated catalytic 19-kDa component of Oplophorus luciferase, nanoKAZ (CDC37-nanoKAZ). A dual-specificity kinase DYRK1A, an importance of which has been highlighted in Alzheimer's disease, was targeted in this study. We established 293T cells stably expressing CDC37-nanoKAZ, and analyzed interaction between CDC37-nanoKAZ and DYRK1A. We revealed that DYRK1A interacted with CDC37-nanoKAZ. Importantly, point mutations that affect autophosphorylation strengthened the interaction, thus improving signal/noise ratio of the interaction relative to non-specific binding of CDC37-nanoKAZ. This high signal/noise ratio enabled screening of chemical library that resulted in identification of a potent inhibitor of DYRK1A, named CaNDY. CaNDY induced selective degradation of DYRK1A, and inhibited catalytic activity of recombinant DYRK1A with IC50 value of 7.9 nM by competing with ATP. This method based on a mutant target kinase and a bioluminescence-eliciting co-chaperone CDC37 could be applicable to evaluation and development of inhibitors targeting other kinases.
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