Benzimidazole inhibitors of protein kinase CK2 potently inhibit the activity of atypical protein kinase Rio1
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- 作者：Konrad Kubiński ; Maciej Masłyk ; Andrzej Orzeszko
- 关键词：Protein kinases ; Small ; molecule inhibitors ; Competitive inhibition ; Toyocamycin ; TIBI
- 刊名：Molecular and Cellular Biochemistry
- 出版年：2017
- 出版时间：February 2017
- 年：2017
- 卷：426
- 期：1-2
- 页码：195-203
- 全文大小：1366KB
- 刊物类别：Biomedical and Life Sciences
- 刊物主题：Biochemistry, general; Medical Biochemistry; Oncology; Cardiology;
- 出版者：Springer US
- ISSN：1573-4919
- 卷排序：426
文摘
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.