Département de chimie moléculaire

None of the already described CK2 inhibitors did fulfill the requirements for successful clin. settings. To find innovative CK2 inhibitors based on new scaffolds, we have performed a high-throughput screening of diverse chem. libraries. We report the identification and characterization of several classes of new inhibitors. Whereas some share characteristics of previously known CK2 inhibitors, others are chem. 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 det. the binding mode of these inhibitors. Interestingly, beside the identification of several nanomolar ATP-competitive inhibitors, one class of chem. 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 chem. compds. are inhibiting CK2 in living cells. Finally, the collected data allowed us to draw the rules about the chem. requirements for CK2 inhibition both in vitro and in a cellular context. [on SciFinder(R)]