Abstract
Recently protein kinases have emerged as some of the most promising drug targets; and therefore, pharmaceutical strategies have been developed to inhibit kinases in the treatment of a variety of diseases. CK2 is a serine/threonine-protein kinase that has been implicated in a number of cellular processes, including maintenance of cell viability, protection of cells from apoptosis, and tumorigenesis. Elevated CK2 activity has been established in a number of cancers where it was shown to promote tumorigenesis via the regulation of the activity of various oncogenes and tumor suppressor proteins. Consequently the development of CK2 inhibitors has been ongoing in preclinical studies, resulting in the generation of a number of CK2-directed compounds. In the present study, an unbiased evaluation of CK2 inhibitors 4,5,6,7-tetrabromo-1H-benzotriazole (TBB), 4,5,6,7-tetrabromo-1H-benzimidazole (TBBz), and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) was carried out to elucidate the mechanism of action as well as inhibitor specificity of these compounds. Utilizing a chemoproteomics approach in conjunction with inhibitor-resistant mutant studies, CK2alpha and CK2alpha' were identified as bona fide targets of TBB, TBBz, and DMAT in cells. However, inhibitor-specific cellular effects were observed indicating that the structurally related compounds had unique biological properties, suggesting differences in inhibitor specificity. Rescue experiments utilizing inhibitor-resistant CK2 mutants were unable to rescue the apoptosis associated with TBBz and DMAT treatment, suggesting the inhibitors had off-target effects. Exploitation of an unbiased chemoproteomics approach revealed a number of putative off-target inhibitor interactions, including the discovery of a novel TBBz and DMAT (but not TBB) target, the detoxification enzyme quinone reductase 2 (QR2). The results described in the present study provide insight into the molecular mechanism of action of the inhibitors as well as drug specificity that will assist in the development of more specific next generation CK2 inhibitors.
Highlights
Protein kinases have emerged as some of the most promising drug targets; and pharmaceutical strategies have been developed to inhibit kinases in the treatment of a variety of diseases
To further characterize the biological responses of cells treated with CK2 inhibitors TBB, TBBz, and DMAT, we examined changes in protein profiles using 2D gel electrophoresis
The role of CK2 in the progression of tumorigenesis has become increasingly evident as the dysregulation of a number of pathways has been attributed to abnormally high levels of CK2 activity
Summary
Protein kinases have emerged as some of the most promising drug targets; and pharmaceutical strategies have been developed to inhibit kinases in the treatment of a variety of diseases. CK2 is a serine/ threonine-protein kinase that has been implicated in a number of cellular processes, including maintenance of cell viability, protection of cells from apoptosis, and tumorigenesis. Elevated CK2 activity has been established in a number of cancers where it was shown to promote tumorigenesis via the regulation of the activity of various oncogenes and tumor suppressor proteins. Targeting protein kinases for therapeutic applications has become a rapidly evolving field with a number of successful inhibitors in clinical studies or approved for treatment of various cancers. Detailed studies have been carried out to elucidate the molecular mechanism of CK2 in tumorigenesis, demonstrating that increased CK2 activity promotes a number of pathways participating in the development of cancer [6, 7]. CK2 has emerged as a promising target for therapeutic intervention in the treatment of cancer
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