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Renaud Prudent

Identification and characterization of protein kinase CK2 inhibitors

Published on 23 November 2009

Thesis presented November 23, 2009

Experimental evidence supports the view that disregulated Protein kinase CK2 is linked to cancers. Elevated CK2 activity in human cancer is an unfavorable prognostic marker. CK2 enhances progression of oncogenesis by regulating various oncogenes, tumor suppressor proteins and protecting anti-apoptotic proteins from caspase-mediated cleavage. Consequently, CK2 has emerged as a therapeutic target and its pharmacological inhibition appears as a promising strategy. Similar to other protein kinases, numerous ATP competitive inhibitors have been identified. However, they display variable effectiveness. Recently, alternative strategies to inhibit this multi-subunit enzyme have been revealed.
Screening of chemical libraries using recombinant CK2a could identify compounds that target either the ATP binding site or exosites. These compounds were structurally characterized by analyzing​ CK2a-inhibitor complexes by means of X-ray structure crystallography or Small-Angle X-ray Scattering (SAXS). These compounds were also evaluated in a novel CK2 cellular activity assay. Several chemically unrelated inhibitors were found to be potent CK2 inhibitor in living cells. Two compounds (ATP-competitive and allosteric, respectively) showed anti-tumor activity, when tested in murine tumor xenograft regression assays.
Taken together, this work leads to the identification of the first allosteric inhibitors of CK2, highlighting a new mode of inhibition of CK2. It also demonstrates that targeting an exosite on CK2 is a viable alternative to ATP-competitive inhibitors. This promises new opportunities by exploiting these new mechanisms of action.

Protein kinase, inhibitors, high-throughput screening, SAXS, X-ray crystallography, tumor xenograft