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Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

  • Mattias F. Lindberg
    Mattias F. Lindberg
    Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France
  • Emmanuel Deau
    Emmanuel Deau
    Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France
  • Jonas Arfwedson
    Jonas Arfwedson
    Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France
  • Nicolas George
    Nicolas George
    Oncodesign, 25-27 avenue du Québec, 91140 Villebon-sur-Yvette, France
  • Pascal George
    Pascal George
    Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France
  • Patricia Alfonso
    Patricia Alfonso
    Enzymlogic, Qube Technology Park, C/Santiago Grisolía, 2, 28760 Madrid, Spain
  • Ana Corrionero
    Ana Corrionero
    Enzymlogic, Qube Technology Park, C/Santiago Grisolía, 2, 28760 Madrid, Spain
  • , and 
  • Laurent Meijer*
    Laurent Meijer
    Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France
    *Email: [email protected]
Cite this: J. Med. Chem. 2023, 66, 6, 4106–4130
Publication Date (Web):March 6, 2023
https://doi.org/10.1021/acs.jmedchem.2c02068
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.

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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)

    • Molecular formula strings (SMILES) (CSV)

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    Cited By

    This article is cited by 2 publications.

    1. Mattias F. Lindberg, Emmanuel Deau, Frédéric Miege, Marie Greverie, Didier Roche, Nicolas George, Pascal George, Laura Merlet, Julie Gavard, Sander J. T. Brugman, Edwin Aret, Paul Tinnemans, René de Gelder, Jan Sadownik, Eva Verhofstad, Dennis Sleegers, Sara Santangelo, Julien Dairou, Álvaro Fernandez-Blanco, Mara Dierssen, Andreas Krämer, Stefan Knapp, Laurent Meijer. Chemical, Biochemical, Cellular, and Physiological Characterization of Leucettinib-21, a Down Syndrome and Alzheimer’s Disease Drug Candidate. Journal of Medicinal Chemistry 2023, 66 (23) , 15648-15670. https://doi.org/10.1021/acs.jmedchem.3c01888
    2. Emmanuel Deau, Mattias F. Lindberg, Frédéric Miege, Didier Roche, Nicolas George, Pascal George, Andreas Krämer, Stefan Knapp, Laurent Meijer. Leucettinibs, a Class of DYRK/CLK Kinase Inhibitors Inspired by the Marine Sponge Natural Product Leucettamine B. Journal of Medicinal Chemistry 2023, 66 (15) , 10694-10714. https://doi.org/10.1021/acs.jmedchem.3c00884

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