Structure-based discovery of novel flavonol inhibitors of human protein kinase CK2

Abstract

Serine/threonine protein kinase CK2 controls vast variety of fundamental processes in cell life; however, despite long period of study, its functional role is not completely determined. CK2 has a significant pathogenic potential and its activity is strictly associated with the development of various kinds of disorders. There are a growing number of facts that inhibitors of CK2 could be used as pharmaceutical agents for the cancer treatment, viral infections, and inflammatory diseases. In this article, we report structural and biological data on the novel synthetic flavonol derivatives, 3-hydroxy-4'-carboxyflavones, possessing a high inhibitory activity toward CK2. With the aid of combinatorial organic synthesis, molecular modeling techniques and biochemical in vitro tests, we studied the structure-activity relationships of flavonol derivatives and developed binding model describing their key intermolecular interactions with the CK2 ATP-binding site. Obtained data show that the synthetic 3-hydroxy-4'-carboxyflavones possess the highest activity among flavonol inhibitors of CK2 known till date.

Identification of a novel potent, selective and cell permeable inhibitor of protein kinase CK2 from the NIH/NCI Diversity Set Library

“…[33,34,[36][37][38][39]). A comparison of the IC 50 values within this group showed that only CK2a and CK2a 0 exhibit values below 10 nM.…”

Design, synthesis and biological evaluation of 2-aminopyrimidinones and their 6-aza-analogs as a new class of CK2 inhibitors

“…It is formed between the carboxyl oxygen of inhibitor and the side chain nitrogen of Lys68. It is worth to mention that this kind of interaction is observed in a number of small-molecule CK2 inhibitors [29][30][31][32][33] . Also, compound 7 forms additional hydrogen bond with Val116 in the hinge region of ATP-acceptor pocket.…”

“…Each test was performed twice in a total reaction volume of 30 mL, containing 6 mg of peptide substrate RRRDDDSDDD (New England Biolabs Ltd., Herts, UK); 10 units of recombinant human CK2 holoenzyme (New England Biolabs); 50 mM adenosine triphosphate (ATP) and g-labeled 32 P ATP, diluted to specific activity 100 mCi/mM; CK2 buffer (20 mM Tris-HCl, pH 7.5; 50 mM KCl; 10 mM MgCl 2 ) and inhibitor in varying concentrations. Incubation time was 20 min at 30 C. The reaction was stopped by adding an equal volume of 10% o-phosphoric acid and the reaction mixture was loaded onto 20-mm discs of phosphocellulose paper (Whatman plc, Kent, UK).…”

Hit identification of CK2 inhibitors by virtual screening

“…The department of Medicinal Chemistry of Institute of Molecular Biology and Genetics NASU is developing, including search, optimization, synthesis and biological evaluation, new inhibitors of CK2 as well as inhibitors of other enzymes for during at least 10 years. Among them, there are many perspective classes, such as 3-carboxy-4(1H)-quinolone derivatives [18], 4,5,6,7-tetrahalogeno-1Hisoindole-1,3(2H)-diones [19], flavone derivatives [20,21] and (thieno[2,3-d]pyrimidine-4-ylthio)carboxylic acid derivatives [22,23].…”