Biochemical and Biophysical Research Communications
2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole: a novel powerful and selective inhibitor of protein kinase CK2
Section snippets
Materials and methods
Protein kinases. Native CK1 (a mixture of α, γ, and δ isoforms [13]) and CK2 were purified from rat liver [14]. The source of the other protein kinases was as previously described or referenced [15].
Synthesis and characterization of 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole. All chemicals and solvents used for the synthesis were purchased from Sigma–Aldrich. Melting points (uncorr.) were measured in open capillary tubes on a Gallenkamp-5 melting point apparatus. Ultraviolet absorption
Results
The structure of the novel inhibitor, 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), is shown in Fig. 1A together with that of the parent compound TBB. In Figs. 1B and C the dose-dependent inhibition of CK2 and CK1, respectively, by the two compounds is shown. DMAT inhibits CK2 more potently than TBB, with an IC50 value around 0.15 μM. In contrast, DMAT is ineffective on CK1 up to 200 μM concentration, whereas 50% inhibition of CK1 activity is attained with 26 μM TBB.
As shown in Fig. 2
Discussion
Based on the data presented the new compound DMAT appears to be the first choice inhibitor of protein kinase CK2 described so far for in vitro and, even more, in vivo investigations, due to a number of properties. First, its Ki value for CK2 inhibition is the lowest reported so far of any other inhibitor of this kinase. Second, the selectivity of DMAT is quite remarkable and comparable to that of TBB, with only DYRK1A, out of a panel of >30 protein kinases, inhibited to the same extent as CK2.
Acknowledgments
The work was supported by grants to L.A.P. and F.M. from the Italian MIUR (PRIN 2002, FIRB and Excellence Center on Signal Transduction) and European Commission (PRO-KINASERESEARCH 503467).
References (19)
- et al.
Protein kinase CK2alpha′ is induced by serum as a delayed early gene and cooperates with Ha-ras in fibroblast transformation
J. Biol. Chem.
(1998) - et al.
The protein kinase CK2 facilitates repair of chromosomal DNA single-strand breaks
Cell
(2004) - et al.
Selectivity of 4,5,6,7-tetrabromobenzotriazole, an ATP site-directed inhibitor of protein kinase CK2 (“casein kinase-2”)
FEBS Lett.
(2001) - et al.
Polyhalogenobenzimidazoles: synthesis and their inhibitory activity against casein kinases
Bioorg. Med. Chem.
(2003) - et al.
Endogenous phosphate acceptor proteins for rat liver cytosolic casein kinases
J. Biol. Chem.
(1981) - et al.
One-thousand-and-one substrates of protein kinase CK2?
FASEB J.
(2003) Protein kinase CK2: structure, regulation and role in cellular decisions of life and death
Biochem. J.
(2003)- et al.
Casein kinase IIα transgene-induced murine lymphoma: relation to theilleriosis in cattle
Science
(1995) - et al.
Tal-1 induces cell acute lymphoblastic leukemia accelerated by casein kinase IIα
EMBO J.
(1996)
Cited by (166)
Proteolysis-targeting chimeras (PROTACs) as novel biotechnology for cancer therapy
2022, Biotechnology in Healthcare, Volume 2: Applications and InitiativesOptimization of pyrazolo[1,5-a]pyrimidines lead to the identification of a highly selective casein kinase 2 inhibitor
2020, European Journal of Medicinal ChemistryCitation Excerpt :A pyrazolo [1,5-a]pyrimidine lead compound has been developed by AstraZeneca, which has also been associated with significant off-target activity including low nanomolar activity on DYRK kinases, DAPKs, and HIPKs [32]. In addition, 4,5,6,7-tetrabromo-1H-benzimidazole [33] has been an important early tool compound stabilized by halogen bonds to the hinge back bone which, however, also showed considerable off-target activity similar to several natural products such as flavones and flavonols with weak CK2 activity and poor pharmacological properties [34]. Thus, despite intensive research on CK2 and their prominent role in the development of cancer and other diseases no selective chemical probes for these closely related kinases have been reported so far.
Pharmacological Interventions to Circadian Clocks and Their Molecular Bases
2020, Journal of Molecular Biology