title: Selectivity of 4,5,6,7-tetrabromobenzimidazole as an ATP-competitive potent inhibitor of protein kinase CK2 from various sources.
abstract: Like the previously reported 4,5,6,7-tetrabromobenzotriazole (TBBt), the structurally related 4,5,6,7-tetrabromobenzimidazole (TBBz) is a selective ATP-competitive inhibitor of protein kinase CK2 from such divergent sources as yeast, rat liver, Neurospora crassa and Candida tropicalis, with K(i) values in the range 0.5-1 microM. It is virtually inactive vs. PKA, PKC, and a very weak inhibitor of protein kinase CK1. The corresponding tetrachlorobenzimidazole (TCBz) is a much weaker inhibitor of CK2, like tetrachlorobenzotriazole (TCBt) relative to TBBt. Bearing in mind the similarity of the van der Waals radii of Br (1.95 A) and CH(3) (2.0 A), the corresponding much less hydrophobic 4,5,6,7-tetramethylbenzotriazole (TMeBt) was prepared and found to be a very weak inhibitor of CK2, as well as of CK1. An unexpected, and significant, difference between TBBt and TBBz are their inhibitory activities vs. the yeast protein kinase PK60S, which phosphorylates, both in vitro and in intact yeast cells, three of the five pp13 kDa ribosomal surface acidic proteins in yeast cells. TBBt was previously noted to be a more effective inhibitor of PK60S than of yeast CK2; by contrast, TBBz is a relatively feeble inhibitor of PK60S, hence more selective than TBBt vs. CK2 in yeast cells. TMeBt was virtually inactive vs PK60S. Like TBBt, TBBz is an additional lead compound for development of more potent inhibitors of CK2.
authors.affiliation: Department of Molecular Biology, Environmental Protection Institute, Catholic University of Lublin, Kraśnicka Av.102, 20-718, Lublin, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Zień
authors.forename: Maria
authors.initials: M
authors.lastname: Bretner
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Zastapiło
authors.forename: Ryszard
authors.initials: R
authors.lastname: Szyszka
authors.forename: David
authors.initials: D
authors.lastname: Shugar
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D041022:Candida tropicalis / Q000201:enzymology; D047390:Casein Kinase II; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D009492:Neurospora crassa / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D014230:Triazoles / Q000494:pharmacology
chemical_list: C475924:4,5,6,7-tetrabromobenzimidazole; C405354:4,5,6,7-tetrabromobenzotriazole; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D014230:Triazoles; D000255:Adenosine Triphosphate; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases