Molecular and Cellular Biochemistry

, Volume 316, Issue 1–2, pp 71–85

Expanding the chemical diversity of CK2 inhibitors

  • Renaud Prudent
  • Virginie Moucadel
  • Miriam López-Ramos
  • Samia Aci
  • Beatrice Laudet
  • Liliane Mouawad
  • Caroline Barette
  • Jacques Einhorn
  • Cathy Einhorn
  • Jean-Noel Denis
  • Gilles Bisson
  • Frédéric Schmidt
  • Sylvaine Roy
  • Laurence Lafanechere
  • Jean-Claude Florent
  • Claude Cochet
Article

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.

Keywords

CK2 Kinase inhibitors Non-competitive 

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

Supplementary material

11010_2008_9828_MOESM1_ESM.xls (21 kb)
Supporting Information Available: Detailed list of compounds with their trivial names and molecular descriptors, machine learning resulting rules used to determine TPSA/ξc threshold are available upon request. MOESM1 (XLS 21 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Renaud Prudent
    • 1
    • 2
    • 3
  • Virginie Moucadel
    • 1
    • 2
    • 3
  • Miriam López-Ramos
    • 4
    • 5
    • 6
    • 7
  • Samia Aci
    • 8
    • 9
  • Beatrice Laudet
    • 1
    • 2
    • 3
  • Liliane Mouawad
    • 6
    • 7
  • Caroline Barette
    • 8
  • Jacques Einhorn
    • 10
  • Cathy Einhorn
    • 10
  • Jean-Noel Denis
    • 10
  • Gilles Bisson
    • 11
  • Frédéric Schmidt
    • 4
    • 5
  • Sylvaine Roy
    • 8
    • 9
  • Laurence Lafanechere
    • 8
  • Jean-Claude Florent
    • 4
    • 5
  • Claude Cochet
    • 1
    • 2
    • 3
  1. 1.INSERM, U873GrenobleFrance
  2. 2.CEA, iRTSV/LTSGrenobleFrance
  3. 3.Université Joseph FourierGrenobleFrance
  4. 4.Institut CurieCentre de RechercheParisFrance
  5. 5.CNRS, UMR 176ParisFrance
  6. 6.Institut Curie, Centre de Recherche, Bâtiment 112Université Paris-SudOrsayFrance
  7. 7.Inserm U759, Bâtiment 112Université Paris-SudOrsayFrance
  8. 8.CEA, iRTSV/CMBAGrenobleFrance
  9. 9.CEA, iRTSV/LBIMGrenobleFrance
  10. 10.Département de Chimie Moléculaire (SERCO), UMR-5250, ICMG FR-2607CNRS Université Joseph FourierGrenoble Cedex 9France
  11. 11.Laboratoire TIMC-IMAG, CNRS/UJF 5525Université de Grenoble Domaine de la MerciLa TroncheFrance

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