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Synthesis and evaluation of new potent inhibitors of CK1 and CDK5, two kinases involved in Alzheimer’s disease

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Abstract

Cyclin-dependent kinase 5 (CDK5) and Casein kinase 1 (CK1) are both involved in the hyperphosphorylation of the Tau protein and in the amyloid-β production, the two major hallmarks of Alzheimer’s disease. In the present paper, we describe the synthesis and biological evaluation of new series of 2,6,9-trisubstituted purines derived from DRF53, a dual specificity inhibitor of the kinase activity of CDK5 (IC50 = 80 nM) and CK1 (IC50 = 10 nM), and are able to prevent in a dose-dependent manner the CK1-dependent production of amyloid-β in a cell model. Several molecules (e.g., 6e, 6g, 7c) displayed potent kinase inhibitory activities against CDK5 and CK1 (IC50 values ranging from 20 to 50 nM) among which a selective inhibitor of CK1 has been identified (5a, IC50 = 60 nM). In addition, some compounds exhibit sub-micromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer’s disease (6g, IC50 = 510 nM).

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Acknowledgments

This research was supported by grants from the “Cancéropole Grand-Ouest” (LM), the “Institut National du Cancer” (INCa “Cancer Détection d’innovations 2006”) (LM), the “Association France-Alzheimer Finistère” (LM), and the “Ligue Nationale contre le Cancer (Grand-Ouest)” (LM).

Pr. Christiane Garbay is gratefully acknowledged for critical reading of the manuscript.

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Authors and Affiliations

  1. Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, and UFR de Pharmacie, 4, avenue de l’Observatoire, 75270, Paris cedex 06, France

    Luc Demange, Nha Thu Hoang & Hervé Galons

  2. CNRS, USR3151, ‘Protein Phosphorylation & Human Disease’ Group, Station Biologique, 29680, Roscoff, Bretagne, France

    Olivier Lozach, Yoan Ferandin & Laurent Meijer

  3. ManRos Therapeutics, Hôtel de Recherche, Centre de Perharidy, 29680, Roscoff, France

    Laurent Meijer

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  1. Luc Demange
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  2. Olivier Lozach
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  3. Yoan Ferandin
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  4. Nha Thu Hoang
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  5. Laurent Meijer
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  6. Hervé Galons
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Correspondence to Luc Demange or Laurent Meijer.

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Demange, L., Lozach, O., Ferandin, Y. et al. Synthesis and evaluation of new potent inhibitors of CK1 and CDK5, two kinases involved in Alzheimer’s disease. Med Chem Res 22, 3247–3258 (2013). https://doi.org/10.1007/s00044-012-0334-1

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  • DOI: https://doi.org/10.1007/s00044-012-0334-1

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