{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T17:42:56Z","timestamp":1760118176294,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T00:00:00Z","timestamp":1735257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["WU 176","PI 806\/2-2"],"award-info":[{"award-number":["WU 176","PI 806\/2-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"discount voucher ba8c87d23218af92 (100.00%)","award":["WU 176","PI 806\/2-2"],"award-info":[{"award-number":["WU 176","PI 806\/2-2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The serine\/threonine kinase CK2 (formerly known as casein kinase II) plays a crucial role in various CNS disorders and is highly expressed in various types of cancer. Therefore, inhibiting this key kinase could be promising for the treatment of these diseases. The CK2 holoenzyme is formed by the recruitment of two catalytically active CK2\u03b1 and\/or CK2\u03b1\u2032 subunits by a regulatory CK2\u03b2 dimer. Starting with the lead furocarbazole W16 (4) inhibiting the CK2\u03b1\/CK2\u03b2 interaction, analogous pyrrolocarbazoles were prepared and tested for their protein\u2013protein interaction inhibition (PPII). The key step of the synthesis was a multicomponent Levy reaction of 2-(indolyl)acetate 6, benzaldehydes 7, and N-substituted maleimides 8. Targeted modifications were performed by the saponification of the tetracyclic ester 9a, followed by the coupling of the resulting acid 10 with diverse amines. The replacement of the O-atom of the lead furocarbazole 4 by an N-atom in pyrrolocarbazoles retained or even increased the inhibition of the CK2\u03b1\/CK2\u03b2 interaction. The large benzyloxazolidinyl moiety of 4 could be replaced by smaller N-substituents without the loss of the PPII. The introduction of larger substituents at the 2-position and\/or at p-position of the phenyl moiety at the 10-position to increase the surface for the inhibition of the PPI did not enhance the inhibition of the CK2\u03b1\/CK2\u03b2 association. The strong inhibition of the CK2\u03b1\/CK2\u03b2 association by the histidine derivative (+)-20a (Ki = 6.1 \u00b5M) translated into a high inhibition of the kinase activity of the CK2 holoenzyme (CK2\u03b12\u03b22, IC50 = 2.5 \u00b5M). Thus, 20a represents a novel lead compound inhibiting CK2 via the inhibition of the association of the CK2\u03b1 and Ck2\u03b2 subunits.<\/jats:p>","DOI":"10.3390\/molecules30010063","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T09:23:36Z","timestamp":1735291416000},"page":"63","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure\u2013Activity Relationship Studies of Tetracyclic Pyrrolocarbazoles Inhibiting Heterotetrameric Protein Kinase CK2"],"prefix":"10.3390","volume":"30","author":[{"given":"Lukas","family":"Kr\u00f6ger","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie, Universit\u00e4t M\u00fcnster, Corrensstra\u00dfe 48, D-48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7140-1907","authenticated-orcid":false,"given":"Sebastian","family":"Borgert","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie, Universit\u00e4t M\u00fcnster, Corrensstra\u00dfe 48, D-48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9619-8450","authenticated-orcid":false,"given":"Miriam","family":"Lauwers","sequence":"additional","affiliation":[{"name":"Institutes I & II of Pharmacology, Center of Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Gleueler Stra\u00dfe 24, D-50931 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michaela","family":"Steinkr\u00fcger","sequence":"additional","affiliation":[{"name":"Institutes I & II of Pharmacology, Center of Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Gleueler Stra\u00dfe 24, D-50931 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0666-2676","authenticated-orcid":false,"given":"Joachim","family":"Jose","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie, Universit\u00e4t M\u00fcnster, Corrensstra\u00dfe 48, D-48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8110-2265","authenticated-orcid":false,"given":"Markus","family":"Pietsch","sequence":"additional","affiliation":[{"name":"Institutes I & II of Pharmacology, Center of Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Gleueler Stra\u00dfe 24, D-50931 Cologne, Germany"},{"name":"Faculty of Applied Natural Sciences, TH K\u00f6ln-University of Applied Sciences, Campus Leverkusen, Campusplatz 1, D-51379 Leverkusen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9030-8417","authenticated-orcid":false,"given":"Bernhard","family":"W\u00fcnsch","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie, Universit\u00e4t M\u00fcnster, Corrensstra\u00dfe 48, D-48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/S0021-9258(18)71184-8","article-title":"The enzymatic phosphorylation of proteins","volume":"211","author":"Burnett","year":"1954","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.cels.2024.05.005","article-title":"The substrate quality of CK2 target sites has a determinant role on their function and evolution","volume":"15","author":"Bradley","year":"2024","journal-title":"Cell Syst."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj20021469","article-title":"Protein kinase CK2: Structure, regulation and role in cellular decisions of life and death","volume":"369","author":"Litchfield","year":"2003","journal-title":"Biochem. J."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Montenarh, M., and G\u00f6tz, C. (2020). Protein kinase CK2 and ion channels (Review). Biomed. Rep., 13.","DOI":"10.3892\/br.2020.1362"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.advenzreg.2008.04.002","article-title":"Protein kinase CK2\u2014A key suppressor of apoptosis","volume":"48","author":"Ahmad","year":"2008","journal-title":"Adv. Enzyme Regul."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1002\/(SICI)1522-2683(19990201)20:2<391::AID-ELPS391>3.0.CO;2-N","article-title":"Protein kinase CK2 and its role in cellular proliferation, development and pathology","volume":"20","author":"Guerra","year":"1999","journal-title":"Electrophoresis"},{"key":"ref_7","first-page":"49","article-title":"Protein kinase CK2 in DNA damage and repair","volume":"5","author":"Montenarh","year":"2016","journal-title":"Transl. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3892\/br.2016.829","article-title":"Protein kinase CK2 in development and differentiation","volume":"6","author":"Montenarh","year":"2017","journal-title":"Biomed. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5320","DOI":"10.1093\/emboj\/20.19.5320","article-title":"Crystal structure of human protein kinase CK2: Insights into basic properties of the CK2 holoenzyme","volume":"20","author":"Niefind","year":"2001","journal-title":"EMBO J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1111\/j.1749-6632.2002.tb04648.x","article-title":"Dynamic Localization\/Association of Protein Kinase CK2 Subunits in Living Cells","volume":"973","author":"Martel","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1006\/abbi.1993.1037","article-title":"Phosphorylation of calmodulin by the catalytic subunit of casein kinase II is inhibited by the regulatory subunit","volume":"300","author":"Bidwai","year":"1993","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/sj.embor.7400115","article-title":"Protein kinase CK2: A new view of an old molecular complex","volume":"5","author":"Filhol","year":"2004","journal-title":"EMBO Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1007\/s00439-016-1661-y","article-title":"De novo mutations in CSNK2A1 are associated with neurodevelopmental abnormalities and dysmorphic features","volume":"135","author":"Okur","year":"2016","journal-title":"Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1002\/humu.23270","article-title":"CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy","volume":"38","author":"Poirier","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/0006-8993(90)90282-G","article-title":"Aberrant casein kinase II in Alzheimer\u2019s disease","volume":"507","author":"Iimoto","year":"1990","journal-title":"Brain Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1212\/WNL.42.3.631","article-title":"Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer\u2019s disease","volume":"42","author":"Arriagada","year":"1992","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6469","DOI":"10.1073\/pnas.95.11.6469","article-title":"alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson\u2019s disease and dementia with lewy bodies","volume":"95","author":"Spillantini","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jns.2007.08.027","article-title":"Localization of CKII beta subunits in Lewy bodies of Parkinson\u2019s disease","volume":"266","author":"Ryu","year":"2008","journal-title":"J. Neurol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Chua, M.M., Ortega, C.E., Sheikh, A., Lee, M., Abdul-Rassoul, H., Hartshorn, K.L., and Dominguez, I. (2017). CK2 in Cancer: Cellular and Biochemical Mechanisms and Potential Therapeutic Target. Pharmaceuticals, 10.","DOI":"10.3390\/ph10010018"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1007\/s00018-009-9154-y","article-title":"Protein kinase CK2 in health and disease: CK2: A key player in cancer biology","volume":"66","author":"Trembley","year":"2009","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1007\/s13402-020-00566-w","article-title":"Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy\u2014Potential clinical relevance","volume":"43","author":"Borgo","year":"2020","journal-title":"Cell Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.ejca.2006.11.021","article-title":"Nuclear localization of protein kinase CK2 catalytic subunit (CK2alpha) is associated with poor prognostic factors in human prostate cancer","volume":"43","author":"Laramas","year":"2007","journal-title":"Eur. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1007\/s11010-022-04558-2","article-title":"Protein kinase CK2\u2014Diverse roles in cancer cell biology and therapeutic promise","volume":"478","author":"Trembley","year":"2023","journal-title":"Mol. Cell. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s11010-005-3077-1","article-title":"Downregulation of CK2 induces apoptosis in cancer cells--a potential approach to cancer therapy","volume":"274","author":"Wang","year":"2005","journal-title":"Mol. Cell. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1517\/13543776.2012.717615","article-title":"Protein kinase CK2 inhibitors: A patent review","volume":"22","author":"Cozza","year":"2012","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1002\/med.20164","article-title":"How druggable is protein kinase CK2?","volume":"30","author":"Cozza","year":"2010","journal-title":"Med. Res. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1021\/acs.jmedchem.2c01523","article-title":"Strategies of Targeting CK2 in Drug Discovery: Challenges, Opportunities, and Emerging Prospects","volume":"66","author":"Chen","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4009","DOI":"10.1021\/acs.jmedchem.2c01887","article-title":"Silmitasertib (CX-4945), a Clinically Used CK2-Kinase Inhibitor with Additional Effects on GSK3beta and DYRK1A Kinases: A Structural Perspective","volume":"66","author":"Grygier","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1158\/1535-7163.MCT-08-1056","article-title":"Anticancer peptide CIGB-300 binds to nucleophosmin\/B23, impairs its CK2-mediated phosphorylation, and leads to apoptosis through its nucleolar disassembly activity","volume":"8","author":"Perera","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1002\/hep.32804","article-title":"Silmitasertib plus gemcitabine and cisplatin first-line therapy in locally advanced\/metastatic cholangiocarcinoma: A Phase 1b\/2 study","volume":"77","author":"Borad","year":"2023","journal-title":"Hepatology"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Schnitzler, A., Gratz, A., Bollacke, A., Weyrich, M., Kuckl\u00e4nder, U., W\u00fcnsch, B., G\u00f6tz, C., Niefind, K., and Jose, J. (2018). A pi-Halogen Bond of Dibenzofuranones with the Gatekeeper Phe113 in Human Protein Kinase CK2 Leads to Potent Tight Binding Inhibitors. Pharmaceuticals, 11.","DOI":"10.3390\/ph11010023"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3846","DOI":"10.1021\/acsptsci.4c00426","article-title":"Discovery of 7,9-Dibromodihydrodibenzofuran as Potent CK2 inhibitor: Synthesis, Biological Evaluation and Structural Studies on E-\/Z isomers","volume":"7","author":"Rumler","year":"2024","journal-title":"ACS Pharmacol. Translat. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2804","DOI":"10.2174\/092986710791859333","article-title":"Non-ATP Competitive Protein Kinase Inhibitors","volume":"17","author":"Garuti","year":"2010","journal-title":"Curr. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kufareva, I., Bestgen, B., Brear, P., Prudent, R., Laudet, B., Moucadel, V., Ettaoussi, M., Sautel, C.F., Krimm, I., and Engel, M. (2019). Discovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-52141-5"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1042\/BJ20070825","article-title":"Structure-based design of small peptide inhibitors of protein kinase CK2 subunit interaction","volume":"408","author":"Laudet","year":"2007","journal-title":"Biochem. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5056","DOI":"10.1039\/C9SC00798A","article-title":"Efficient development of stable and highly functionalised peptides targeting the CK2\u03b1\/CK2\u03b2 protein-protein interaction","volume":"10","author":"Iegre","year":"2019","journal-title":"Chem. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1002\/cmdc.201800786","article-title":"Design of CK2\u03b2-Mimicking Peptides as Tools to Study the CK2\u03b1\/CK2\u03b2 Interaction in Cancer Cells","volume":"14","author":"Lindenblatt","year":"2019","journal-title":"ChemMedChem"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3016","DOI":"10.1016\/j.bmc.2018.05.011","article-title":"Novel non-ATP competitive small molecules targeting the CK2 \u03b1\/\u03b2 interface","volume":"26","author":"Brear","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s11010-008-9821-6","article-title":"Identification of chemical inhibitors of protein-kinase CK2 subunit interaction","volume":"316","author":"Laudet","year":"2008","journal-title":"Mol. Cell. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1002\/cmdc.202000040","article-title":"Synthesis and SAR of tetracyclic inhibitors of protein kinase CK2 derived from furocarbazole W16","volume":"15","author":"Daniliuc","year":"2020","journal-title":"ChemMedChem"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug Del. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9607","DOI":"10.1016\/j.tet.2008.07.045","article-title":"Diastereodivergence and appendage diversity in the multicomponent synthesis of aryl-pyrrolo-tetrahydrocarbazoles","volume":"64","author":"Royer","year":"2008","journal-title":"Tetrahedron"},{"key":"ref_43","first-page":"6297","article-title":"Stereochemistry of the Levy reaction","volume":"45","year":"2018","journal-title":"Eur. J. Org. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1021\/acs.oprd.8b00193","article-title":"Thermal Stability Assessment of Peptide Coupling Reagents Commonly Used in Pharmaceutical Manufacturing","volume":"22","author":"Sperry","year":"2018","journal-title":"Org. Process Res. Dev."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Pietsch, M., Viht, K., Schnitzler, A., Ekambaram, R., Steinkr\u00fcger, M., Enkvist, E., Nienberg, C., Nickelsen, A., Lauwers, M., and Jose, J. (2020). Unexpected CK2\u03b2-antagonistic functionality of bisubstrate inhibitors targeting protein kinase CK2. Bioorg. Chem., 96.","DOI":"10.1016\/j.bioorg.2020.103608"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1002\/elps.200900514","article-title":"A CE-based assay for human protein kinase CK2 activity measurement and inhibitor screening","volume":"31","author":"Gratz","year":"2010","journal-title":"Electrophoresis"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1110\/ps.037770.108","article-title":"The interaction of CK2\u03b1 and CK2\u03b2, the subunits of protein kinase CK2, requires CK2\u03b2 in a preformed conformation and is enthalpically driven","volume":"17","author":"Raaf","year":"2008","journal-title":"Protein Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/j.1432-1033.1991.tb15982.x","article-title":"Isolation and characterization of recombinant human casein kinase II subunits \u03b1 and \u03b2 from bacteria","volume":"198","author":"Grankowski","year":"1991","journal-title":"Eur. J. Biochem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/1\/63\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T17:01:31Z","timestamp":1760115691000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/1\/63"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,27]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["molecules30010063"],"URL":"https:\/\/doi.org\/10.3390\/molecules30010063","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2024,12,27]]}}}