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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2023, 66, 6, 4106-4130
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    Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases
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    • Mattias F. Lindberg
      Mattias F. Lindberg
      Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France
      More by Mattias F. Lindberg
      Orcidhttps://orcid.org/0000-0002-9734-8163
    • Emmanuel Deau
      Emmanuel Deau
      Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France
      More by Emmanuel Deau
    • Jonas Arfwedson
      Jonas Arfwedson
      Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France
      More by Jonas Arfwedson
    • Nicolas George
      Nicolas George
      Oncodesign, 25-27 avenue du Québec, 91140 Villebon-sur-Yvette, France
      More by Nicolas George
    • Pascal George
      Pascal George
      Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France
      More by Pascal George
    • Patricia Alfonso
      Patricia Alfonso
      Enzymlogic, Qube Technology Park, C/Santiago Grisolía, 2, 28760 Madrid, Spain
      More by Patricia Alfonso
    • Ana Corrionero
      Ana Corrionero
      Enzymlogic, Qube Technology Park, C/Santiago Grisolía, 2, 28760 Madrid, Spain
      More by Ana Corrionero
    • Laurent Meijer*
      Laurent Meijer
      Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France
      *Email: [email protected]
      More by Laurent Meijer
      Orcidhttps://orcid.org/0000-0003-3511-4916
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2023, 66, 6, 4106–4130
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    https://doi.org/10.1021/acs.jmedchem.2c02068
    Published March 6, 2023
    Copyright © 2023 American Chemical Society
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    Abstract

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    Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) play a large variety of cellular functions and are involved in several diseases (cognitive disorders, diabetes, cancers, etc.). There is, thus, growing interest in pharmacological inhibitors as chemical probes and potential drug candidates. This study presents an unbiased evaluation of the kinase inhibitory activity of a library of 56 reported DYRK/CLK inhibitors on the basis of comparative, side-by-side, catalytic activity assays on a panel of 12 recombinant human kinases, enzyme kinetics (residence time and Kd), in-cell inhibition of Thr-212-Tau phosphorylation, and cytotoxicity. The 26 most active inhibitors were modeled in the crystal structure of DYRK1A. The results show a rather large diversity of potencies and selectivities among the reported inhibitors and emphasize the difficulties to avoid “off-targets” in this area of the kinome. The use of a panel of DYRKs/CLKs inhibitors is suggested to analyze the functions of these kinases in cellular processes.

    Copyright © 2023 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c02068.

    • Detailed synthesis protocols of the 13 compounds synthesized at Perha Pharmaceuticals and their corresponding 1H NMR analyses and 13C NMR spectra; CAS #, MW, log P, molecular formula strings (SMILES), and the reported selectivity of the DYRK/CLK inhibitors investigated in this study; assay parameters for the tested protein kinases in the radiometric and proximity assays; the Thr212-Tau phosphorylation assays with all 56 compounds in SH-SY5Y-Tau4R cells; and the molecular modeling of 26 inhibitors in DYRK1A (PDF)

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2023, 66, 6, 4106–4130
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.2c02068
    Published March 6, 2023
    Copyright © 2023 American Chemical Society
    Request reuse permissions

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