The novel potent and specific CK2 inhibitors - 4,5,6,7-tetrahalogeno-1H-isoindole-1,3(2H)-diones (TID) was identified by high-throughput docking of OTAVA compound collection containing more than 90,000 diverse small organic compounds in the ATP binding site of human CK2. Best-scored compounds in vitro tests showed their inhibitory activity towards CK2. This fact encouraged us to investigate TID derivatives more comprehensively. A combinatorial library of TID derivatives was synthesized and inhibitory activities of an additional 68 compounds were determined in vitro. The most active compound is 2-(4,5,6,7-tetraiodo-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoic acid with IC50 values 0.15 µM.
These inhibitors are ATP-competitive and they only minimally inhibit the activities of protein kinases DYRK1a, MSK1, GSK3 and CDK5. A mode of binding of TIDs in the CK2 ATP-binding site is proposed and compared to that for structurally related analogues —tetrabromobenzotriazole derivatives.
These inhibitors, and additional derivatives could be successfully used for further structural optimization and biological testing.