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RESEARCH Protein Kinase Inhibitors CK2 Inhibitors 4,5,6,7-tetrahalogeno-1H-isoindole-1,3(2H)-diones (TID)

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.
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.

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