Generic placeholder image

Current Computer-Aided Drug Design

Author(s): Samer Haidar*, Franziska Jürgens, Dagmar Aichele and Joachim Jose

DOI: 10.2174/1573409916666200311150744

DownloadDownload PDF Flyer Cite As
In Silico and In Vitro Studies of Natural Compounds as Human CK2 Inhibitors

Page: [323 - 331] Pages: 9

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

Background: Casein Kinase 2 (CK2) is a ubiquitous cellular serine-threonine kinase with broad spectrum of substrates. This enzyme is widely expressed in eukaryotic cells and is overexpressed in different human cancers. Thus, the inhibition of CK2 can induce the physiological process of apoptosis leading to tumor cell death.

Objectives: Selecting natural inhibitors toward the target enzyme using database mining.

Methods: With our continuous effort to discover new compounds with CK2 inhibitory effect, several commercial natural databases were searched using molecular modeling approach and the selected compounds were evaluated in vitro.

Results: Three compounds were selected as candidates and evaluated in vitro using CK2 holoenzyme, their effect on three cancer cell lines was determined. The selected candidates were weak inhibitors toward the target enzyme, only one compound showed moderate effect on cell viability.

Conclusion: Several natural databases were screened, compounds were selected and tested in vitro. Despite the unexpected low inhibitory activity of the tested compounds, this study can help in directing the search of potent CK2 inhibitors and better understand the binding requirements of the ATP competitive inhibitors.

Keywords: In silico screening, CK2, natural compounds, inhibitors, in vitro, cancer.

Graphical Abstract

[1]
Ivanov, K.I.; Puustinen, P.; Gabrenaite, R.; Vihinen, H.; Rönnstrand, L.; Valmu, L.; Kalkkinen, N.; Mäkinen, K. Phosphorylation of the potyvirus capsid protein by protein kinase CK2 and its relevance for virus infection. Plant Cell, 2003, 15(9), 2124-2139.
[http://dx.doi.org/10.1105/tpc.012567] [PMID: 12953115]
[2]
Axtell, R.C.; Xu, L.; Barnum, S.R.; Raman, C. CD5-CK2 binding/activation-deficient mice are resistant to experimental autoimmune encephalomyelitis: protection is associated with diminished populations of IL-17-expressing T cells in the central nervous system. J. Immunol., 2006, 177(12), 8542-8549.
[http://dx.doi.org/10.4049/jimmunol.177.12.8542] [PMID: 17142752]
[3]
Murtaza, I.; Wang, H.X.; Feng, X.; Alenina, N.; Bader, M.; Prabhakar, B.S.; Li, P.F. Down-regulation of catalase and oxidative modification of protein kinase CK2 lead to the failure of apoptosis repressor with caspase recruitment domain to inhibit cardiomyocyte hypertrophy. J. Biol. Chem., 2008, 283(10), 5996-6004.
[http://dx.doi.org/10.1074/jbc.M706466200] [PMID: 18171680]
[4]
(a)Haidar, S.; Meyers, A.; Bollacke, A.; Jose, J. Synthesis and biological evaluation of 2,6-di(furan-3-yl)anthracene-9, 10-dione as an inhibitor of human protein kinase CK2. Pharmazie, 2015, 70(12), 772-776..
[PMID: 26817273]
(b)Haidar, S.; Aichele, D.; Birus, R.; Hielscher, J.; Laitinen, T.; Poso, A.; Jose, J. in vitro and in silico evaluation of bikaverin as a potent inhibitor of human protein kinase CK2., Molecules, 2019, 24(7)E1380.
[http://dx.doi.org/10.3390/molecules24071380] [PMID: 30965682]
(c)Olgen, S.; Götz, C.; Jose, J. Synthesis and biological evaluation of 3-(substituted-benzylidene)-1,3-dihydro-indolin derivatives as human protein kinase CK2 and p60(c-Src) tyrosine kinase inhibitors. Biol. Pharm. Bull., 2007, 30(4), 715-718..
[http://dx.doi.org/10.1248/bpb.30.715] [PMID: 17409508]
(d)Jabor Gozzi, G.; Bouaziz, Z.; Winter, E.; Daflon-Yunes, N.; Aichele, D.; Nacereddine, A.; Marminon, C.; Valdameri, G.; Zeinyeh, W.; Bollacke, A.; Guillon, J.; Lacoudre, A.; Pinaud, N.; Cadena, S.M.; Jose, J.; Le Borgne, M.; Di Pietro, A. Converting potent indeno[1,2-b]indole inhibitors of protein kinase CK2 into selective inhibitors of the breast cancer resistance protein ABCG2. J. Med. Chem., 2015, 58(1), 265-277.
[http://dx.doi.org/10.1021/jm500943z] [PMID: 25272055]
[5]
Cozza, G.; Pinna, L.A. Casein kinases as potential therapeutic targets. Expert Opin. Ther. Targets, 2016, 20(3), 319-340.
[http://dx.doi.org/10.1517/14728222.2016.1091883] [PMID: 26565594]
[6]
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod., 2012, 75(3), 311-335.
[http://dx.doi.org/10.1021/np200906s] [PMID: 22316239]
[7]
(a)Cozza, G. The development of ck2 inhibitors: from traditional pharmacology to in silico rational drug design., Pharmaceuticals (Basel), 2017, 10(1)E26.
[http://dx.doi.org/10.3390/ph10010026] [PMID: 28230762]
(b)Cozza, G.; Pinna, L.A.; Moro, S. Protein kinase CK2 inhibitors: a patent review. Expert Opin. Ther. Pat., 2012, 22(9), 1081-1097.
[http://dx.doi.org/10.1517/13543776.2012.717615] [PMID: 22908959]
[8]
Haidar, S.; Bouaziz, Z.; Marminon, C.; Laitinen, T.; Poso, A.; Le Borgne, M.; Jose, J. Development of pharmacophore model for indeno[1,2-b]indoles as human protein kinase CK2 inhibitors and database mining. Pharmaceuticals (Basel), 2017, 10(1),E8
[http://dx.doi.org/10.3390/ph10010008] [PMID: 28075359]
[9]
Gratz, A.; Götz, C.; Jose, J. A CE-based assay for human protein kinase CK2 activity measurement and inhibitor screening. Electrophoresis, 2010, 31(4), 634-640.
[http://dx.doi.org/10.1002/elps.200900514] [PMID: 20162588]
[10]
Xue, L.Y.; Chiu, S.M.; Oleinick, N.L. Staurosporine-induced death of MCF-7 human breast cancer cells: a distinction between caspase-3-dependent steps of apoptosis and the critical lethal lesions. Exp. Cell Res., 2003, 283(2), 135-145.
[http://dx.doi.org/10.1016/S0014-4827(02)00032-0] [PMID: 12581734]
[11]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[12]
Molecular Operating Environment (MOE), C. C. G. I., 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7;. , 2013.
[13]
RCSB PDB. (Available from:. https://www.rcsb.org/pdb/explore/explore.do)
[14]
Tsai, Y.L.; Chiu, C.C.; Y-F., Chen J.; Chan, K.C.; Lin, S.D. Cytotoxic effects of Echinacea purpurea flower extracts and cichoric acid on human colon cancer cells through induction of apoptosis. J. Ethnopharmacol., 2012, 143(3), 914-919.
[http://dx.doi.org/10.1016/j.jep.2012.08.032] [PMID: 22971663]
[15]
Santhanam, R.K.; Ahmad, S.; Abas, F.; Safinar Ismail, I.; Rukayadi, Y.; Tayyab Akhtar, M.; Shaari, K. Bioactive constituents of zanthoxylum rhetsa bark and its cytotoxic Potential against B16-F10 melanoma cancer and normal human dermal fibroblast (HDF) cell lines. Molecules, 2016, 21(6)E652
[http://dx.doi.org/10.3390/molecules21060652] [PMID: 27231889]
[16]
(a)Toppo, E.; Darvin, S.S.; Esakkimuthu, S.; Stalin, A.; Balakrishna, K.; Sivasankaran, K.; Pandikumar, P.; Ignacimuthu, S.; Al-Dhabi, N.A. Antihyperlipidemic and hepatoprotective effects of Gardenin A in cellular and high fat diet fed rodent models., Chem. Biol. Interact., 2017, 269, 9-17..
[http://dx.doi.org/10.1016/j.cbi.2017.03.013 ] [PMID: 28351695]
(b)Chiu, S.P.; Wu, M.J.; Chen, P.Y.; Ho, Y.R.; Tai, M.H.; Ho, C.T.; Yen, J.H. Neurotrophic action of 5-hydroxylated polymethoxyflavones: 5-demethylnobiletin and gardenin A stimulate neuritogenesis in PC12 cells. J. Agric. Food Chem., 2013, 61(39), 9453-9463.
[http://dx.doi.org/10.1021/jf4024678] [PMID: 24003765]
[17]
Salic, A.; Mitchison, T.J. A chemical method for fast and sensitive detection of DNA synthesis in vivo. Proc. Natl. Acad. Sci. USA, 2008, 105(7), 2415-2420.
[http://dx.doi.org/10.1073/pnas.0712168105] [PMID: 18272492]
[18]
Baier, A.; Nazaruk, J.; Galicka, A.; Szyszka, R. Inhibitory influence of natural flavonoids on human protein kinase CK2 isoforms: effect of the regulatory subunit. Mol. Cell. Biochem., 2018, 444(1-2), 35-42.
[http://dx.doi.org/10.1007/s11010-017-3228-1] [PMID: 29188536]
[19]
Haidar, S.; Jabbour, M.; Al-Khayat, M.A.; Aichele, D.; Jose, J. Synthesis and biological evaluation of novel 2 (4`-hydroxynaphthyl) chromen-4-one as a CK2 inhibitor. Pharmazie, 2018, 73(4), 191-195.
[PMID: 29609684]
[20]
Li, S.; Pan, M.H.; Lai, C.S.; Lo, C.Y.; Dushenkov, S.; Ho, C.T. Isolation and syntheses of polymethoxyflavones and hydroxylated polymethoxyflavones as inhibitors of HL-60 cell lines. Bioorg. Med. Chem., 2007, 15(10), 3381-3389.
[http://dx.doi.org/10.1016/j.bmc.2007.03.021] [PMID: 17391969]
[21]
Sugiyama, S.; Umehara, K.; Kuroyanagi, M.; Ueno, A.; Taki, T. Studies on the differentiation inducers of myeloid leukemic cells from Citrus species. Chem. Pharm. Bull. (Tokyo), 1993, 41(4), 714-719.
[http://dx.doi.org/10.1248/cpb.41.714] [PMID: 8508474]