| Abstract
| - Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whoseabnormally high constitutive activity is suspected to underlie its pathogenic potential inneoplasia and infective diseases. Thus, CK2 inhibitors designed to dissect the signalingpathways affected by this kinase, in perspective, may give rise to pharmacological tools. Oneof the most successful CK2 inhibitors is TBB (4,5,6,7-tetrabromobenzotriazole). Here we showthat its inhibitory properties can be markedly improved by generating adducts in which N2 isreplaced by a carbon atom bound to a variety of polar functions. The most efficient inhibitor is4,5,6,7-tetrabromo-2-(dimethylamino)benzimidazole (2c) followed by the methylsulfanyl (8),isopropylamino (2e), and amino (2a) congeners. All these compounds display Ki values <100nM (40 nM in the case of 2c). 2c induces apoptosis of Jurkat cells more readily than TBB(DC50 value 2.7 vs 17 μM) and, unlike TBB, it does not display any side effect on mitochondriapolarization up to 10 μM concentration. Molecular modeling of the CK2−2c complex, based onthe crystal structure of the CK2−TBB complex suggests that a number of additional apolarcontacts between its two methyl groups and hydrophobic residues nearby could account for itssuperior inhibitory properties. Consequently, 2c is even more susceptible than TBB to mutationsof the unique hydrophobic residues V66 and/or I174 to alanine. We propose to adopt 2c as firstchoice CK2 inhibitor instead of TBB, especially for in cell studies.
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