title: Benzimidazole inhibitors of protein kinase CK2 potently inhibit the activity of atypical protein kinase Rio1.
abstract: Benzimidazole derivatives of 5,6-dichlorobenzimidazole 1-β-D-ribofuranoside (DRB) comprise the important class of protein kinase CK2 inhibitors. Depending on the structure, benzimidazoles inhibit CK2 with different selectivity and potency. Besides CK2, the compounds can inhibit, with similar activity, other classical eukaryotic protein kinases (e.g. PIM, DYRK, and PKD). The present results show that a majority of the most common CK2 inhibitors can affect the atypical kinase Rio1 in a nanomolar range. Kinetic data confirmed the mode of action of benzimidazoles as typical ATP-competitive inhibitors. In contrast to toyocamycin-the first discovered small-molecule inhibitor of Rio1-the most potent representative of benzimidazoles TIBI (IC50= 0.09 µM, Ki= 0.05 µM) does not influence the oligomeric state of the Rio1 kinase. Docking studies revealed that TIBI can occupy the ATP-binding site of Rio1 in a manner similar to toyocamycin, and enhances the thermostability of the enzyme.
authors.affiliation: Department of Molecular Biology, Institute of Biotechnology, The John Paul II Catholic University of Lublin, ul. Konstantynów 1i, 20-708, Lublin, Poland.
authors.forename: Konrad
authors.initials: K
authors.lastname: Kubiński
authors.affiliation: Department of Molecular Biology, Institute of Biotechnology, The John Paul II Catholic University of Lublin, ul. Konstantynów 1i, 20-708, Lublin, Poland. maciekm@kul.pl.
authors.forename: Maciej
authors.initials: M
authors.lastname: Masłyk
authors.affiliation: Institute of Chemistry, Warsaw Life Sciences University, ul. Nowoursynowska 159c, 02-787, Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Orzeszko
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020134:Catalytic Domain; D004795:Enzyme Stability; D006358:Hot Temperature; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014127:Toyocamycin / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; C469385:RIOK1 protein, human; D014127:Toyocamycin
keywords: Competitive inhibition; Protein kinases; Small-molecule inhibitors; TIBI; Toyocamycin