The selectivity of inhibitors of protein kinase CK2: an update

Author:

Pagano Mario A.12,Bain Jenny3,Kazimierczuk Zygmunt4,Sarno Stefania12,Ruzzene Maria12,Di Maira Giovanni12,Elliott Matthew3,Orzeszko Andrzej5,Cozza Giorgio1,Meggio Flavio1,Pinna Lorenzo A.12

Affiliation:

1. Department of Biological Chemistry and CNR Institute of Neurosciences, University of Padova, viale G. Colombo 3, 35131 Padova, Italy

2. Venetian Institute for Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy

3. Division of Signal Transduction Therapy and Medical Research Council, Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, Scotland, U.K.

4. Laboratory of Experimental Pharmacology, Polish Academy of Sciences Medical Research Center, 5 Pawinskiego St. 02-106 Warsaw, Poland

5. Military University of Technology, 2 Kaliskiego Street, 00-908 Warsaw, Poland

Abstract

CK2 (casein kinase 2) is a very pleiotropic serine/threonine protein kinase whose abnormally high constitutive activity has often been correlated to pathological conditions with special reference to neoplasia. The two most widely used cell permeable CK2 inhibitors, TBB (4,5,6,7-tetrabromo-1H-benzotriazole) and DMAT (2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole), are marketed as quite specific CK2 blockers. In the present study we show, by using a panel of approx. 80 protein kinases, that DMAT and its parent compound TBI (or TBBz; 4,5,6,7-tetrabromo-1H-benzimidazole) are potent inhibitors of several other kinases, with special reference to PIM (provirus integration site for Moloney murine leukaemia virus)1, PIM2, PIM3, PKD1 (protein kinase D1), HIPK2 (homeodomain-interacting protein kinase 2) and DYRK1a (dual-specificity tyrosine-phosphorylated and -regulated kinase 1a). In contrast, TBB is significantly more selective toward CK2, although it also inhibits PIM1 and PIM3. In an attempt to improve selectivity towards CK2 a library of 68 TBB/TBI-related compounds have been tested for their ability to discriminate between CK2, PIM1, HIPK2 and DYRK1a, ending up with seven compounds whose efficacy toward CK2 is markedly higher than that toward the second most inhibited kinase. Two of these, K64 (3,4,5,6,7-pentabromo-1H-indazole) and K66 (1-carboxymethyl-2-dimethylamino-4,5,6,7-tetrabromo-benzimidazole), display an overall selectivity much higher than TBB and DMAT when tested on a panel of 80 kinases and display similar efficacy as inducers of apoptosis.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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