2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole: a novel powerful and selective inhibitor of protein kinase CK2

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Abstract

Protein kinase CK2 is a highly pleiotropic enzyme whose high constitutive activity is suspected to be instrumental to the enhancement of the tumour phenotype and to the propagation of infectious diseases. Here we describe a novel compound, 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), which is superior to the commonly used specific CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) in several respects. DMAT displays the lowest Ki value ever reported for a CK2 inhibitor (40 nM); it is cell permeable and its efficacy on cultured cells, both in terms of endogenous CK2 inhibition and induction of apoptosis, is several fold higher than that of TBB. The selectivity of DMAT assayed on a panel of >30 protein kinases is comparable to that of TBB, with the additional advantage of being ineffective on protein kinase CK1 up to 200 μM. These properties make DMAT the first choice CK2 inhibitor for in vivo studies available to date.

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Materials and methods

Protein kinases. Native CK1 (a mixture of α, γ, and δ isoforms [13]) and CK2 were purified from rat liver [14]. The source of the other protein kinases was as previously described or referenced [15].

Synthesis and characterization of 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole. All chemicals and solvents used for the synthesis were purchased from Sigma–Aldrich. Melting points (uncorr.) were measured in open capillary tubes on a Gallenkamp-5 melting point apparatus. Ultraviolet absorption

Results

The structure of the novel inhibitor, 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), is shown in Fig. 1A together with that of the parent compound TBB. In Figs. 1B and C the dose-dependent inhibition of CK2 and CK1, respectively, by the two compounds is shown. DMAT inhibits CK2 more potently than TBB, with an IC50 value around 0.15 μM. In contrast, DMAT is ineffective on CK1 up to 200 μM concentration, whereas 50% inhibition of CK1 activity is attained with 26 μM TBB.

As shown in Fig. 2

Discussion

Based on the data presented the new compound DMAT appears to be the first choice inhibitor of protein kinase CK2 described so far for in vitro and, even more, in vivo investigations, due to a number of properties. First, its Ki value for CK2 inhibition is the lowest reported so far of any other inhibitor of this kinase. Second, the selectivity of DMAT is quite remarkable and comparable to that of TBB, with only DYRK1A, out of a panel of >30 protein kinases, inhibited to the same extent as CK2.

Acknowledgments

The work was supported by grants to L.A.P. and F.M. from the Italian MIUR (PRIN 2002, FIRB and Excellence Center on Signal Transduction) and European Commission (PRO-KINASERESEARCH 503467).

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