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Expanding the chemical diversity of CK2 inhibitors

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Abstract

None of the already described CK2 inhibitors did fulfill the requirements for successful clinical settings. In order to find innovative CK2 inhibitors based on new scaffolds, we have performed a high-throughput screening of diverse chemical libraries. We report here the identification and characterization of several classes of new inhibitors. Whereas some share characteristics of previously known CK2 inhibitors, others are chemically unrelated and may represent new opportunities for the development of better CK2 inhibitors. By combining structure-activity relationships with a docking procedure, we were able to determine the binding mode of these inhibitors. Interestingly, beside the identification of several nanomolar ATP-competitive inhibitors, one class of chemical inhibitors displays a non-ATP competitive mode of inhibition, a feature that suggests that CK2 possess distinct druggable binding sites. For the most promising inhibitors, selectivity profiling was performed. We also provide evidence that some chemical compounds are inhibiting CK2 in living cells. Finally, the collected data allowed us to draw the rules about the chemical requirements for CK2 inhibition both in vitro and in a cellular context.

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Abbreviations

CK2:

Casein kinase 2

ATP:

Adenosine triphosphate

IQA:

IndoloQuinAzolin derivative

TBCA:

Tetrabromocinnamic acid

TBB:

4,5,6,7-Tetrabromo-1-benzotriazole

DMAT:

2-DiMethylAmino-4,5,6,7-tetrabromo-1H-benzimidazole

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Acknowledgments

This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Centre National pour la Recherche Scientifique (CNRS), the Commissariat à l’Energie Atomique (CEA), the Institut Curie, the Ligue Nationale Contre le Cancer (équipe labellisée 2007), the Institut National du Cancer (Grant Number 57). The authors thanks the Drug Synthesis & Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI, for the library of low-molecular-weight compounds, the ChemAxon company (http://www.chemaxon.com) for allowing academics to freely use their software, especially here the Standardizer and the Calculator Plugins to compute descriptors and the MarvinView package, for viewing structure files in our home-made software, PhenoScreen.

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Authors and Affiliations

  1. INSERM, U873, Grenoble, 38054, France

    Renaud Prudent, Virginie Moucadel, Beatrice Laudet & Claude Cochet

  2. CEA, iRTSV/LTS, Grenoble, 38054, France

    Renaud Prudent, Virginie Moucadel, Beatrice Laudet & Claude Cochet

  3. Université Joseph Fourier, Grenoble, France

    Renaud Prudent, Virginie Moucadel, Beatrice Laudet & Claude Cochet

  4. Institut Curie, Centre de Recherche, 26 Rue d’Ulm, Paris, 75248, France

    Miriam López-Ramos, Frédéric Schmidt & Jean-Claude Florent

  5. CNRS, UMR 176, 26 Rue d’Ulm, Paris, 75248, France

    Miriam López-Ramos, Frédéric Schmidt & Jean-Claude Florent

  6. Institut Curie, Centre de Recherche, Bâtiment 112, Université Paris-Sud, Orsay, 91405, France

    Miriam López-Ramos & Liliane Mouawad

  7. Inserm U759, Bâtiment 112, Université Paris-Sud, Orsay, 91405, France

    Miriam López-Ramos & Liliane Mouawad

  8. CEA, iRTSV/CMBA, Grenoble, 38054, France

    Samia Aci, Caroline Barette, Sylvaine Roy & Laurence Lafanechere

  9. CEA, iRTSV/LBIM, Grenoble, 38054, France

    Samia Aci & Sylvaine Roy

  10. Département de Chimie Moléculaire (SERCO), UMR-5250, ICMG FR-2607, CNRS Université Joseph Fourier, BP-53, Grenoble Cedex 9, 38041, France

    Jacques Einhorn, Cathy Einhorn & Jean-Noel Denis

  11. Laboratoire TIMC-IMAG, CNRS/UJF 5525, Université de Grenoble Domaine de la Merci, La Tronche, 38710, France

    Gilles Bisson

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  1. Renaud Prudent
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Correspondence to Claude Cochet.

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11010_2008_9828_MOESM1_ESM.xls

Supporting Information Available: Detailed list of compounds with their trivial names and molecular descriptors, machine learning resulting rules used to determine TPSA/ξ c threshold are available upon request. MOESM1 (XLS 21 kb)

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Prudent, R., Moucadel, V., López-Ramos, M. et al. Expanding the chemical diversity of CK2 inhibitors. Mol Cell Biochem 316, 71–85 (2008). https://doi.org/10.1007/s11010-008-9828-z

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