Content area
Full Text
Mol Cell Biochem (2008) 316:7185 DOI 10.1007/s11010-008-9828-z
Expanding the chemical diversity of CK2 inhibitors
Renaud Prudent Virginie Moucadel Miriam Lpez-Ramos Samia Aci Beatrice Laudet Liliane Mouawad Caroline Barette Jacques Einhorn Cathy Einhorn Jean-Noel Denis Gilles Bisson Frdric Schmidt Sylvaine Roy Laurence Lafanechere Jean-Claude Florent Claude Cochet
Received: 19 May 2008 / Accepted: 29 May 2008 / Published online: 18 June 2008 Springer Science+Business Media, LLC. 2008
Abstract None of the already described CK2 inhibitors did fulll the requirements for successful clinical settings. In order to nd innovative CK2 inhibitors based on new scaffolds, we have performed a high-throughput screening of diverse chemical libraries. We report here the identication 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 identication 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 drug-gable binding sites. For the most promising inhibitors, selectivity proling 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
Electronic supplementary material The online version of this article (doi:http://dx.doi.org/10.1007/s11010-008-9828-z
Web End =10.1007/s11010-008-9828-z ) contains supplementary material, which is available to authorized users.
R. Prudent V. Moucadel B. Laudet C. Cochet (&)
INSERM, U873, Grenoble 38054, France e-mail: [email protected]
R. Prudent V. Moucadel B. Laudet C. Cochet
CEA, iRTSV/LTS, Grenoble 38054, France
R. Prudent V. Moucadel B. Laudet C. Cochet
Universit Joseph Fourier, Grenoble, France
M. Lpez-Ramos F. Schmidt J.-C. Florent
Institut Curie, Centre de Recherche, 26 Rue dUlm, Paris 75248, France
M. Lpez-Ramos F. Schmidt J.-C. Florent
CNRS, UMR 176, 26 Rue dUlm, Paris 75248, France
M. Lpez-Ramos L. Mouawad
Institut Curie, Centre de Recherche, Btiment 112, Universit Paris-Sud, Orsay 91405, France
M. Lpez-Ramos L. Mouawad
Inserm U759, Btiment 112, Universit Paris-Sud, Orsay 91405, France
S. Aci C. Barette...