Screening of DTP Compound Libraries for CK2 Inhibitors with Focus on Natural Products
Various compound libraries of the Drug Therapeutic Program (DTP) of the NIH/NCI were screened against the catalytic subunit and the tetrameric holoenzyme of protein kinase CK2. Different IC50 values were obtained for the two CK2 molecules. In the case of nortangeretin, the IC50 value was 0.34 μM for the catalytic subunit and 15 μM for the holoenzyme. In the case of coumestrol, opposite results were obtained, i.e., high IC50 for the CK2α subunit (2.7 μM) and a lower IC50 value for the holoenzyme (0.19 μM).
From the many compounds identified to inhibit CK2, we have selected 14 different compounds and listed them according to their CK2α/CK2 holoenzyme IC50 ratio.
Four compounds were tested on a panel of seven cell lines revealing considerable differences in the degree of CK2 inhibition inside the cells.
KeywordsProtein kinase CK2 Casein kinase 2 Eukaryotic protein kinases CMGC kinases Signal transduction pathways Protein kinase inhibitors Small molecule compounds DTP compound libraries
We thank the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, USA, for providing us with plated and vialed samples from the various compound sets. The advice of Dr. David Newman at the start of the investigation is particularly acknowledged. We also thank the many students who have been involved in some of the screenings presented in this report. This work was supported in part by Grosserer M. Brogaard og Hustrus Mindefond and the Danish Council for Independent Research-Natural Sciences (grant 1323-00212A to B. Guerra), the Danish Cancer Society (grant 252-1109-210), and the Danish Research Council (grant 21-04-0517) to O.-G. Issinger.
- 23.Klopffleisch K, Issinger O-G, Niefind K (2012) Low-density crystal packing of human protein kinase CK2 catalytic subunit in complex with resorufin or other ligands: a tool to study the unique hinge-region plasticity of the enzyme without packing bias. Acta Crystallogr D Biol Crystallogr 68:883–892. doi: 10.1107/S0907444912016587 CrossRefPubMedGoogle Scholar
- 28.Tamm I, Bablanian R, Nemes MM et al (1961) Relationship between structure of benzimidazole derivatives and selective virus inhibitory activity. Inhibition of poliovirus multiplication and cytopathic effects by 2-(alpha-hydroxybenzyl)-benzimidazole, and its 5-chloroderivative. J Exp Med 113:625–656CrossRefPubMedCentralPubMedGoogle Scholar
- 30.Farabegoli F, Vettraino M, Manerba M et al (2012) Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways. Eur J Pharm Sci 47:729–738. doi: 10.1016/j.ejps.2012.08.012 CrossRefPubMedGoogle Scholar
- 31.Vettraino M, Manerba M, Govoni M, Di Stefano G (2013) Galloflavin suppresses lactate dehydrogenase activity and causes MYC downregulation in Burkitt lymphoma cells through NAD/NADH-dependent inhibition of sirtuin-1. Anticancer Drugs 24:862–870. doi: 10.1097/CAD.0b013e328363ae50 CrossRefPubMedGoogle Scholar
- 34.Dixit D, Sharma V, Ghosh S et al (2012) Inhibition of Casein kinase-2 induces p53-dependent cell cycle arrest and sensitizes glioblastoma cells to tumor necrosis factor (TNFα)-induced apoptosis through SIRT1 inhibition. Cell Death Dis 3:e271. doi: 10.1038/cddis.2012.10 CrossRefPubMedCentralPubMedGoogle Scholar
- 54.Rezaei-Sadabady R, Eidi A, Zarghami N, Barzegar A (2014) Intracellular ROS protection efficiency and free radical-scavenging activity of quercetin and quercetin-encapsulated liposomes. Artif Cells Nanomed Biotechnol 1–7. doi: 10.3109/21691401.2014.926456
- 62.Meggio F, Boldyreff B, Issinger O-G, Pinna LA (1994) Casein kinase 2 down-regulation and activation by polybasic peptides are mediated by acidic residues in the 55-64 region of the beta-subunit. A study with calmodulin as phosphorylatable substrate. Biochemistry 33:4336–4342CrossRefPubMedGoogle Scholar