4,5,6,7-tetrahalogeno-1H-isoindole-1,3(2H)-diones (TID)

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.

Figure 1. The binding mode of TID46 in the CK2 active site. Hydrogen bonds are shown by the dotted lines.

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.

• Evaluation of 4,5,6,7-tetrahalogeno-1H-isoindole-1,3(2H)-diones as inhibitors of human protein kinase CK2. Golub AG, Yakovenko OY, Prykhod'ko AO, Lukashov SS, Bdzhola VG, Yarmoluk SM. Mol Cell Biochem. Biochim Biophys Acta. 2008, 1784(1): 143-149.
• Pat.: UA69165 А, С07D215/00, 2004-08-16. Application of 4,5,6,7-tetrahalogeno-1,3-isoindolinediones as protein kinase CK2 inhibitors. Golub A.G., Yakovenko O.Ya., Yarmoluk S.M., Dubinina G.G., Bdzhola V.G., Prykhod'ko A.O.