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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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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DOI: https://doi.org/10.1007/s11010-008-9828-z