Abstract
Evaluation of in vitro activity and SAR study of the novel hetarylamino-3-aryl-1H-indazole derivatives as inhibitors of protein kinase CK2
Highlights
Serine/threonine protein kinase CK2 was discovered among the first ones in 1954 [1]
In the previous work we have described chemical synthesis of the novel 5-hetarylamino-1H-indazole derivatives as prominent inhibitors of human protein kinase CK2 [10]
Earlier we have found new promising CK2 inhibitors with IC50 values in a range 0.007– 0.1 μM in in vitro assay with radiolabeled ATP [15] among the 4-substituted quinazoline derivatives of 5-amino-3-arylindazoles 1–3 [20]
Summary
Serine/threonine protein kinase CK2 was discovered among the first ones in 1954 [1]. Despite a long history of CK2 investigations, a number of its functions are not completely determined. In contrast to the common protein kinases CK2 cannot be turned off by the mechanisms such as phosphorylation or dephosphorylation, second messenger binding and reversible association with regulatory subunits, but can be only ‘‘modulated’’ by means of the mechanisms, which are still not completely understood [3]. The ATP binding pocket of CK2 is smaller than that of the other protein kinases, that is why the ATP competitive inhibitors with higher selectivity for CK2 could be developed. CK2 has high pleiotropicity (CK2 phosphorylates more than 500 proteins) [5] – most of the substrates have been found to be transcriptional factors (60), effectors of DNA/RNA structure (50), signaling proteins (more than 80), a limited number of metabolic enzymes and even over 40 viruses use CK2 to phosphorylate essential proteins in their life cycle [6]. Smallmolecular inhibitors of CK2 would be important compounds for the development of clinical agents
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