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.
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Research Article|
October 15 2008
The selectivity of inhibitors of protein kinase CK2: an update
Mario A. Pagano;
Mario A. Pagano
1
*Department of Biological Chemistry and CNR Institute of Neurosciences, University of Padova, viale G. Colombo 3, 35131 Padova, Italy
†Venetian Institute for Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy
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Jenny Bain;
Jenny Bain
1
‡Division of Signal Transduction Therapy and Medical Research Council, Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Zygmunt Kazimierczuk;
Zygmunt Kazimierczuk
2
§Laboratory of Experimental Pharmacology, Polish Academy of Sciences Medical Research Center, 5 Pawinskiego St. 02-106 Warsaw, Poland
2Correspondence may be addressed to either of these authors (email lorenzo.pinna@unipd.it or zygmunt_kazimierczuk@sggw.pl).
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Stefania Sarno;
Stefania Sarno
*Department of Biological Chemistry and CNR Institute of Neurosciences, University of Padova, viale G. Colombo 3, 35131 Padova, Italy
†Venetian Institute for Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy
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Maria Ruzzene;
Maria Ruzzene
*Department of Biological Chemistry and CNR Institute of Neurosciences, University of Padova, viale G. Colombo 3, 35131 Padova, Italy
†Venetian Institute for Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy
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Giovanni Di Maira;
Giovanni Di Maira
*Department of Biological Chemistry and CNR Institute of Neurosciences, University of Padova, viale G. Colombo 3, 35131 Padova, Italy
†Venetian Institute for Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy
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Matthew Elliott;
Matthew Elliott
‡Division of Signal Transduction Therapy and Medical Research Council, Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Andrzej Orzeszko;
Andrzej Orzeszko
∥Military University of Technology, 2 Kaliskiego Street, 00-908 Warsaw, Poland
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Giorgio Cozza;
Giorgio Cozza
*Department of Biological Chemistry and CNR Institute of Neurosciences, University of Padova, viale G. Colombo 3, 35131 Padova, Italy
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Flavio Meggio;
Flavio Meggio
*Department of Biological Chemistry and CNR Institute of Neurosciences, University of Padova, viale G. Colombo 3, 35131 Padova, Italy
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Lorenzo A. Pinna
*Department of Biological Chemistry and CNR Institute of Neurosciences, University of Padova, viale G. Colombo 3, 35131 Padova, Italy
†Venetian Institute for Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy
2Correspondence may be addressed to either of these authors (email lorenzo.pinna@unipd.it or zygmunt_kazimierczuk@sggw.pl).
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Publisher: Portland Press Ltd
Received:
February 06 2008
Revision Received:
June 10 2008
Accepted:
June 30 2008
Accepted Manuscript online:
June 30 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 415 (3): 353–365.
Article history
Received:
February 06 2008
Revision Received:
June 10 2008
Accepted:
June 30 2008
Accepted Manuscript online:
June 30 2008
Citation
Mario A. Pagano, Jenny Bain, Zygmunt Kazimierczuk, Stefania Sarno, Maria Ruzzene, Giovanni Di Maira, Matthew Elliott, Andrzej Orzeszko, Giorgio Cozza, Flavio Meggio, Lorenzo A. Pinna; The selectivity of inhibitors of protein kinase CK2: an update. Biochem J 1 November 2008; 415 (3): 353–365. doi: https://doi.org/10.1042/BJ20080309
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