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Birus R, El-Awaad E, Ballentin L, et al. 4,5,7-Trisubstituted indeno[1,2-b]indole inhibits CK2 activity in tumor cells equivalent to CX-4945 and shows strong anti-migratory effects. FEBS Open Bio. 2021;doi: 10.1002/2211-5463.13346.
Birus, R., El-Awaad, E., Ballentin, L., Alchab, F., Aichele, D., Ettouati, L., Götz, C., Le Borgne, M., & Jose, J. (2021). 4,5,7-Trisubstituted indeno[1,2-b]indole inhibits CK2 activity in tumor cells equivalent to CX-4945 and shows strong anti-migratory effects. FEBS open bio, . https://doi.org/10.1002/2211-5463.13346
Birus, Robin, et al. "4,5,7-Trisubstituted indeno[1,2-b]indole inhibits CK2 activity in tumor cells equivalent to CX-4945 and shows strong anti-migratory effects." FEBS open bio vol. (2021). doi: https://doi.org/10.1002/2211-5463.13346
Birus R, El-Awaad E, Ballentin L, Alchab F, Aichele D, Ettouati L, Götz C, Le Borgne M, Jose J. 4,5,7-Trisubstituted indeno[1,2-b]indole inhibits CK2 activity in tumor cells equivalent to CX-4945 and shows strong anti-migratory effects. FEBS Open Bio. 2021 Dec 06; doi: 10.1002/2211-5463.13346. Epub 2021 Dec 06. PMID: 34873879.
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FEBS Open Bio. 2021 Dec 06; doi: 10.1002/2211-5463.13346. Epub 2021 Dec 06.

4,5,7-Trisubstituted indeno[1,2-b]indole inhibits CK2 activity in tumor cells equivalent to CX-4945 and shows strong anti-migratory effects.

FEBS open bio

Robin Birus, Ehab El-Awaad, Laurens Ballentin, Faten Alchab, Dagmar Aichele, Laurent Ettouati, Claudia Götz, Marc Le Borgne, Joachim Jose

Affiliations

  1. Institute of Pharmaceutical and Medicinal Chemistry, Westfälische Wilhelms-Universtität Münster, Germany.
  2. Department of Pharmacology, Faculty of Medicine, Assiut University, Egypt.
  3. EEA 4446 Bioactive Molecules and Medicinal Chemistry, Faculté de Pharmacie-ISPB, SFR Santé Lyon-Est CNRS UMS3453-INSERM US7, Université Claude Bernard Lyon 1, Université de Lyon, France.
  4. Faculty of Pharmacy, Manara University, Latakia, Syria.
  5. CNRS UMR 5246 Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Faculté de Pharmacie, ISPB, Université Lyon 1, Université de Lyon, France.
  6. Medical Biochemistry and Molecular Biology, Saarland University, Germany.
  7. Small Molecules for Biological Targets Team, Centre de recherche en cancérologie de Lyon, Centre Léon Bérard, CNRS 5286, INSERM 1052, Université Claude Bernard Lyon 1, Université de Lyon, France.

PMID: 34873879 DOI: 10.1002/2211-5463.13346

Abstract

Highly pleiotropic and constitutively active protein kinase CK2 is a key target in cancer therapy, but only one small-molecule inhibitor has reached clinical trials-CX-4945. In this study, we present the indeno[1,2-b]indole derivative 5-isopropyl-4-methoxy-7-methyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (5a-2) that decreased the intracellular CK2 activity in A431, A549, and LNCaP tumor cell lines analogous to CX-4945 (> 75% inhibition at 20 µm) and similarly blocked CK2-specific Akt phosphorylation in LNCaP cells. Cellular uptake analysis demonstrated higher intracellular concentrations of 5a-2 (408.3 nm) compared with CX-4945 (119.3 nm). This finding clarifies the comparable effects of both compounds on the intracellular CK2 activity despite their different inhibitory potency in vitro [IC

© 2021 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Keywords: CK2; HPLC-MS/MS; indeno[1,2-b]indole; live-cell imaging; pharmacokinetics

References

  1. Litchfield DW. Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem J. 2003;369:1-15. - PubMed
  2. Burnett G, Kennedy EP. The enzymatic phosphorylation of proteins. J Biol Chem. 1954;211:969-80. - PubMed
  3. Montenarh M, Götz C. Protein kinase CK2 and ion channels (Review). Biomed Rep. 2020;13:55-64. - PubMed
  4. Faust M, Montenarh M. Subcellular localization of protein kinase CK2 - A key to its function? Cell Tissue Res. 2000;301:329-40. - PubMed
  5. de Villavicencio-Diaz TN, Rabalski AJ, Litchfield DW. Protein kinase CK2: Intricate relationships within regulatory cellular networks. Pharmaceuticals. 2017;10:27-45. - PubMed
  6. Salvi M, Sarno S, Cesaro L, Nakamura H, Pinna LA. Extraordinary pleiotropy of protein kinase CK2 revealed by weblogo phosphoproteome analysis. Bba-Mol Cell Res. 2009;1793:847-59. - PubMed
  7. D'Amore C, Salizzato V, Borgo C, Cesaro L, Pinna LA, Salvi M. A journey through the cytoskeleton with protein kinase CK2. Curr Protein Pept Sc. 2019;20:547-62. - PubMed
  8. Guerra B, Issinger OG. Protein kinase CK2 and its role in cellular proliferation, development and pathology. Electrophoresis. 1999;20:391-408. - PubMed
  9. Ahmad KA, Wang G, Unger G, Slaton J, Ahmed K. Protein kinase CK2 - a key suppressor of apoptosis. Adv Enzyme Regul. 2008;48:179-87. - PubMed
  10. Ahmed K, Yenice S, Davis A, Goueli SA. Association of casein kinase 2 with nuclear chromatin in relation to androgenic regulation of rat prostate. P Natl Acad Sci USA. 1993;90:4426-30. - PubMed
  11. Montenarh M, Gotz C. Ecto-protein kinase CK2, the neglected form of CK2. Biomed Rep. 2018;8:307-13. - PubMed
  12. Chua MMJ, Ortega CE, Sheikh A, Lee M, Abdul-Rassoul H, Hartshorn KL, et al. CK2 in cancer: Cellular and biochemical mechanisms and potential therapeutic target. Pharmaceuticals. 2017;10:18-47. - PubMed
  13. Silva-Pavez E, Tapia JC. Protein kinase CK2 in cancer energetics, Front. Oncol. 2020;10:893-902. - PubMed
  14. Ruzzene M, Pinna LA. Addiction to protein kinase CK2: A common denominator of diverse cancer cells? Bba-Proteins Proteom. 2010;1804:499-504. - PubMed
  15. Borgo C, D'Amore C, Sarno S, Salvi M, Ruzzene M. Protein kinase CK2: A potential therapeutic target for diverse human diseases. Signal Transduct Target Ther. 2021;6:183-202. - PubMed
  16. Tawfic S, Yu S, Wang H, Faust R, Davis A, Ahmed K. Protein kinase CK2 signal in neoplasia. Histol Histopathol. 2001;16:573-82. - PubMed
  17. Ruzzene M, Penzo D, Pinna LA. Protein kinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) induces apoptosis and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells. Biochem J. 2002;364:41-7. - PubMed
  18. Guo CH, Yu SH, Davis AT, Wang HM, Green JE, Ahmed K. A potential role of nuclear matrix-associated protein kinase CK2 in protection against drug-induced apoptosis in cancer cells. J Biol Chem. 2001;276:5992-9. - PubMed
  19. Slaton JW, Unger GM, Sloper DT, Davis AT, Ahmed K. Induction of apoptosis by antisense CK2 in human prostate cancer xenograft model. Mol Cancer Res. 2004;2:712-21. - PubMed
  20. Wang GX, Unger G, Ahmad KA, Slaton JW, Ahmed K. Downregulation of CK2 induces apoptosis in cancer cells - a potential approach to cancer therapy. Mol Cell Biochem. 2005;274:77-84. - PubMed
  21. Duncan JS, Litchfield DW. Too much of a good thing: The role of protein kinase CK2 in tumorigenesis and prospects for therapeutic inhibition of CK2. Bba-Proteins Proteom. 2008;1784:33-47. - PubMed
  22. Cozza G. The development of CK2 inhibitors: From traditional pharmacology to in silico rational drug design. Pharmaceuticals. 2017;10:26-58. - PubMed
  23. Perea SE, Reyes O, Baladron I, Perera Y, Farina H, Gil J, et al. CIGB-300, a novel proapoptotic peptide that impairs the CK2 phosphorylation and exhibits anticancer properties both in vitro and in vivo. Mol Cell Biochem. 2008;316:163-7. - PubMed
  24. Perera Y, Ramos Y, Padron G, Caballero E, Guirola O, Caligiuri LG, et al. CIGB-300 anticancer peptide regulates the protein kinase CK2-dependent phosphoproteome. Mol Cell Biochem. 2020;470:63-75. - PubMed
  25. Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, O'Brien SE, et al. CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res. 2010;70:10288-98. - PubMed
  26. Pierre F, Chua PC, O'Brien SE, Siddiqui-Jain A, Bourbon P, Haddach M, et al. Discovery and SAR of 5-(3-Chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer. J Med Chem. 2011;54:635-54. - PubMed
  27. Son YH, Song JS, Kim SH, Kim J. Pharmacokinetic characterization of CK2 inhibitor CX-4945. Arch Pharm Res. 2013;36:840-5. - PubMed
  28. Zakharia K, Miyabe K, Wang Y, Wu DH, Moser CD, Borad MJ, et al. Preclinical in vitro and in vivo evidence of an antitumor effect of CX-4945, a casein kinase II inhibitor, in cholangiocarcinoma. Transl Oncol. 2019;12:143-53. - PubMed
  29. D'Amore C, Borgo C, Sarno S, Salvi M. Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy - potential clinical relevance. Cell Oncol. 2020;43:1003-16. - PubMed
  30. Martins LR, Lucio P, Melao A, Antunes I, Cardoso BA, Stansfield R, et al. Activity of the clinical-stage CK2-specific inhibitor CX-4945 against chronic lymphocytic leukemia. Leukemia. 2014;28:179-82. - PubMed
  31. Takahashi K, Setoguchi T, Tsuru A, Saitoh Y, Nagano S, Ishidou Y, et al. Inhibition of casein kinase 2 prevents growth of human osteosarcoma. Oncol Rep. 2017;37:1141-7. - PubMed
  32. Zanin S, Borgo C, Girardi C, O'Brien SE, Miyata Y, Pinna LA, et al. Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant cells. PLoS One. 2012;7:e49193. - PubMed
  33. Girardi C, Ottaviani D, Pinna LA, Ruzzene M. Different persistence of the cellular effects promoted by protein kinase CK2 inhibitors CX-4945 and TDB. Biomed Res Int. 2015;2015:736. - PubMed
  34. Arriazu E, Vicente C, Pippa R, Peris I, Martinez-Balsalobre E, Garcia-Ramirez P, et al. A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia. Blood Cancer J. 2020;10:3-17. - PubMed
  35. Hundsdörfer C, Hemmerling HJ, Götz C, Totzke F, Bednarski P, Le Borgne M, et al. Indeno[1,2-b]indole derivatives as a novel class of potent human protein kinase CK2 inhibitors. Bioorg Med Chem. 2012;20:2282-9. - PubMed
  36. Alchab F, Ettouati L, Bouaziz Z, Bollacke A, Delcros JG, Gertzen CGW, et al. Synthesis, biological evaluation and molecular modeling of substituted indeno[1,2-b]indoles as inhibitors of human protein kinase CK2. Pharmaceuticals. 2015;8:279-302. - PubMed
  37. Haidar S, Bouaziz Z, Marminon C, Laitinen T, Poso A, Le Borgne M, et al. Development of pharmacophore model for indeno[1,2-b]indoles as human protein kinase CK2 inhibitors and database mining. Pharmaceuticals. 2017;10:8-20. - PubMed
  38. Gozzi GJ, Bouaziz Z, Winter E, Daflon-Yunes N, Aichele D, Nacereddine A, et al. 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;58:265-77. - PubMed
  39. El-Awaad E, Birus R, Marminon C, Bouaziz Z, Ballentin L, Aichele D, et al. Broad-spectrum anticancer activity and pharmacokinetic properties of a prenyloxy-substituted indeno[1,2-b]indole derivative, discovered as CK2 inhibitor. Pharmaceuticals. 2021;14:542-58. - PubMed
  40. Bloch S, Nejman-Falenczyk B, Pierzynowska K, Piotrowska E, Wegrzyn A, Marminon C, et al. Inhibition of shiga toxin-converting bacteriophage development by novel antioxidant compounds. J Enzyme Inhib Med Chem. 2018;33:639-50. - PubMed
  41. Haidar S, Marminon C, Aichele D, Nacereddine A, Zeinyeh W, Bouzina A, et al. QSAR model of indeno[1,2-b]indole derivatives and identification of N-isopentyl-2-methyl-4,9-dioxo-4,9-Dihydronaphtho[2,3-b]furan-3-carboxamide as a potent CK2 inhibitor. Molecules. 2020;25:97-112. - PubMed
  42. Gratz A, Götz C, Jose J. A CE-based assay for human protein kinase CK2 activity measurement and inhibitor screening. Electrophoresis. 2010;31:634-40. - PubMed
  43. Galla F, Bourgeois C, Lehmkuhl K, Schepmann D, Soeberdt M, Lotts T, et al. Effects of polar kappa receptor agonists designed for the periphery on ATP-induced Ca2+ release from keratinocytes. MedChemComm. 2016;7:317-26. - PubMed
  44. McCloy RA, Rogers S, Caldon CE, Lorca T, Castro A, Burgess A. Partial inhibition of Cdk1 in G(2) phase overrides the SAC and decouples mitotic events. Cell Cycle. 2014;13:1400-12. - PubMed
  45. Schmitt BM, Boewe AS, Götz C, Philipp SE, Urbschat S, Oertel J, et al. CK2 activity mediates the aggressive molecular signature of glioblastoma multiforme by inducing nerve/glial antigen (NG)2 expression. Cancers. 2021;13:1678-94. - PubMed
  46. Faust M, Schuster N, Montenarh M. Specific binding of protein kinase CK2 catalytic subunits to tubulin. FEBS Lett. 1999;462:51-6. - PubMed
  47. Schneider CC, Götz C, Hessenauer A, Günther J, Kartarius S, Montenarh M. Down-regulation of CK2 activity results in a decrease in the level of cdc25c phosphatase in different prostate cancer cell lines. Mol Cell Biochem. 2011;356:177-84. - PubMed
  48. Rahnel H, Viht K, Lavogina D, Mazina O, Haljasorg T, Enkvist E, et al. A selective biligand inhibitor of CK2 increases caspase-3 activity in cancer cells and inhibits platelet aggregation. ChemMedChem. 2017;12:1723-36. - PubMed
  49. Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, et al. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer; 2020. - PubMed
  50. Di Maira G, Salvi M, Arrigoni G, Marin O, Sarno S, Brustolon F, et al. Protein kinase CK2 phosphorylates and upregulates Akt/PKB. Cell Death Differ. 2005;12:668-77. - PubMed
  51. Smith D, Artursson P, Avdeef A, Di L, Ecker GF, Faller B, et al. Passive lipoidal diffusion and carrier-mediated cell uptake are both important mechanisms of membrane permeation in drug disposition. Mol Pharm. 2014;11:1727-38. - PubMed
  52. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46:3-26. - PubMed
  53. Poirier A, Lave T, Portmann R, Brun ME, Senner F, Kansy M, et al. Design, data analysis, and simulation of in vitro drug transport kinetic experiments using a mechanistic in vitro model. Drug Metab Dispos. 2008;36:2434-44. - PubMed
  54. Trepat X, Chen ZZ, Jacobson K. Cell migration. Compr Physiol. 2012;2:2369-92. - PubMed
  55. Kim J, Kim SH. CK2 inhibitor CX-4945 blocks TGF-beta 1-induced epithelial-to-mesenchymal transition in A549 human lung adenocarcinoma cells. PLoS One. 2013;8:e74342. - PubMed
  56. Borgo C, Ruzzene M. Chapter two - Protein kinase CK2 inhibition as a pharmacological strategy in Advances in Protein Chemistry and Structural Biology (Donev R, ed) pp. 23-46, Academic Press. - PubMed
  57. Mateus A, Treyer A, Wegler C, Karlgren M, Matsson P, Artursson P. Intracellular drug bioavailability: A new predictor of system dependent drug disposition. Sci Rep-Uk. 2017;7:1-12. - PubMed
  58. Intemann J, Saidu NEB, Schwind L, Montenarh M. ER stress signaling in ARPE-19 cells after inhibition of protein kinase CK2 by CX-4945. Cell Signal. 2014;26:1567-75. - PubMed
  59. Li QW, Zong Y, Li K, Jie XH, Hong JX, Zhou XS, et al. Involvement of endothelial CK2 in the radiation induced perivascular resistant niche (PVRN) and the induction of radioresistance for non-small cell lung cancer (NSCLC) cells. Biol Res. 2019;52:22-30. - PubMed
  60. Wells CI, Drewry DH, Pickett JE, Tjaden A, Kramer A, Muller S, et al. Development of a potent and selective chemical probe for the pleiotropic kinase CK2. Cell Chem Biol. 2021;28:546-58. - PubMed
  61. Schmitt B, Sippl C, Urbschat S, Oertel J, Laschke M, Menger M, et al. Protein kinase CK2 regulates the expression of nerve/glial antigen (Ng)2 in glioblastoma. Neuro-Oncol. 2019;21:47. - PubMed
  62. Valastyan S, Weinberg RA. Tumor metastasis: Molecular insights and evolving paradigms. Cell. 2011;147:275-92. - PubMed
  63. Wang GX, Ahmad KA, Ahmed K. Modulation of death receptor-mediated apoptosis by CK2. Mol Cell Biochem. 2005;274:201-5. - PubMed
  64. Padilla-Benavides T, Haokip DT, Yoon Y, Reyes-Gutierrez P, Rivera-Perez JA, Imbalzano AN. CK2-dependent phosphorylation of the Brg1 chromatin remodeling enzyme occurs during mitosis. Int J Mol Sci. 2020;21:923-42. - PubMed
  65. Kramerov AA, Golub AG, Bdzhola VG, Yarmoluk SM, Ahmed K, Bretner M, et al. Treatment of cultured human astrocytes and vascular endothelial cells with protein kinase CK2 inhibitors induces early changes in cell shape and cytoskeleton. Mol Cell Biochem. 2011;349:125-37. - PubMed
  66. Ruiz C, Martins JR, Rudin F, Schneider S, Dietsche T, Fischer CA, et al. Enhanced expression of ANO1 in head and neck squamous cell carcinoma causes cell migration and correlates with poor prognosis. PLoS One. 2012;7:e43265. - PubMed
  67. Pinto MC, Schreiber R, Lerias J, Ousingsawat J, Duarte A, Amaral M, et al. Regulation of TMEM16A by CK2 and its role in cellular proliferation. Cells. 2020;9:1138-52. - PubMed

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