{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:28:52Z","timestamp":1790436532225,"version":"4.1.0"},"reference-count":97,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,3,25]],"date-time":"2020-03-25T00:00:00Z","timestamp":1585094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["RTI2018-093539-B-I00"],"award-info":[{"award-number":["RTI2018-093539-B-I00"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The design of multitarget drugs (MTDs) has become an innovative approach for the search of effective treatments in complex diseases such as cancer. In this work, we communicate our efforts in the design of multi-targeting histone deacetylase (HDAC) and protein kinase CK2 inhibitors as a novel therapeutic strategy against cancer. Using tetrabromobenzotriazole (TBB) and 2-dimethylamino-4,5,6,7-tetrabromo-benzimidazole (DMAT) as scaffolds for CK2 inhibition, and a hydroxamate to coordinate the zinc atom present in the active site of HDAC (zinc binding group, ZBG), new multitarget inhibitors have been designed and synthesized. According to the in vitro assays, N-Hydroxy-6-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)hexanamide (11b) is the most interesting compound, with IC50 values of 0.66; 1.46 and 3.67 \u00b5M. for HDAC6; HDAC1 and CK2; respectively. Cellular assays on different cancer cell lines rendered promising results for N-Hydroxy-8-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)octanamide (11d). This inhibitor presented the highest cytotoxic activity, proapoptotic capability, and the best mitochondria-targeting and multidrug-circumventing properties, thus being the most promising drug candidate for further in vivo studies.<\/jats:p>","DOI":"10.3390\/molecules25071497","type":"journal-article","created":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T05:55:16Z","timestamp":1585893316000},"page":"1497","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 Inhibitors"],"prefix":"10.3390","volume":"25","author":[{"given":"Regina","family":"Mart\u00ednez","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica y Bioqu\u00edmica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, Alcorc\u00f3n, 28925 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1822-7142","authenticated-orcid":false,"given":"Bruno","family":"Di Geronimo","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica y Bioqu\u00edmica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, Alcorc\u00f3n, 28925 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miryam","family":"Pastor","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica y Bioqu\u00edmica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, Alcorc\u00f3n, 28925 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Mar\u00eda","family":"Zapico","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica y Bioqu\u00edmica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, Alcorc\u00f3n, 28925 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7229-8289","authenticated-orcid":false,"given":"Claire","family":"Coderch","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica y Bioqu\u00edmica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, Alcorc\u00f3n, 28925 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2908-8213","authenticated-orcid":false,"given":"Rostyslav","family":"Panchuk","sequence":"additional","affiliation":[{"name":"Institute of Cell Biology, NAS of Ukraine, Drahomanov Str. 14\/16, 79005 Lviv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Skorokhyd","sequence":"additional","affiliation":[{"name":"Institute of Cell Biology, NAS of Ukraine, Drahomanov Str. 14\/16, 79005 Lviv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0516-3231","authenticated-orcid":false,"given":"Maciej","family":"Maslyk","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Faculty of Biotechnology and Environment Sciences, The John Paul II Catholic University of Lublin, 20-718 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2984-4672","authenticated-orcid":false,"given":"Ana","family":"Ramos","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica y Bioqu\u00edmica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, Alcorc\u00f3n, 28925 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1101-0373","authenticated-orcid":false,"given":"Beatriz","family":"de Pascual-Teresa","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica y Bioqu\u00edmica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, Alcorc\u00f3n, 28925 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1038\/449993a","article-title":"Mixing cocktails","volume":"449","author":"Sawyers","year":"2007","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.drudis.2006.11.008","article-title":"Multi-target therapeutics: When the whole is greater than the sum of the parts","volume":"12","author":"Zimmermann","year":"2007","journal-title":"Drug Discov. Today"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5232","DOI":"10.1158\/1078-0432.CCR-07-1385","article-title":"Targeted Agents: The Rules of Combination","volume":"13","author":"Kwak","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/nrd2188","article-title":"The trouble with making combination drugs","volume":"5","author":"Simon","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6523","DOI":"10.1021\/jm058225d","article-title":"Designed Multiple Ligands. An Emerging Drug Discovery Paradigm","volume":"48","author":"Morphy","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4722","DOI":"10.2174\/092986711797535344","article-title":"Designed Multiple Ligands for Cancer Therapy","volume":"18","author":"Boyle","year":"2011","journal-title":"Curr. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1021\/acs.jmedchem.8b00760","article-title":"Polypharmacology by Design: A Medicinal Chemist\u2019s Perspective on Multitargeting Compounds","volume":"62","author":"Proschak","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4345","DOI":"10.1016\/j.bmcl.2006.05.051","article-title":"N-(1,2-Diphenylethyl)piperazines: A new class of dual serotonin\/noradrenaline reuptake inhibitor","volume":"16","author":"Bish","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5640","DOI":"10.1021\/jm0605785","article-title":"New Opioid Designed Multiple Ligand from Dmt-Tic and Morphinan Pharmacophores","volume":"49","author":"Neumeyer","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1021\/jm301653f","article-title":"Systematic Exploration of Dual-Acting Modulators from a Combined Medicinal Chemistry and Biology Perspective","volume":"56","author":"Bornot","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.2174\/092986712801215883","article-title":"Designed Multiple Ligands: Basic Research vs. Clinical Outcomes","volume":"19","author":"Costantino","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1021\/jm7009364","article-title":"Multi-target-Directed Ligands To Combat Neurodegenerative Diseases","volume":"51","author":"Cavalli","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1021\/acsmedchemlett.9b00039","article-title":"Harnessing Polypharmacology with Medicinal Chemistry","volume":"10","author":"Bolognesi","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1021\/cb300054n","article-title":"Structural Determinants of Protein Kinase CK2 Regulation by Autoinhibitory Polymerization","volume":"7","author":"Lolli","year":"2012","journal-title":"ACS Chem. Biol."},{"key":"ref_15","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_16","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.2174\/092986711796150423","article-title":"The Dark Side of Protein Kinase CK2 Inhibition","volume":"18","author":"Cozza","year":"2011","journal-title":"Curr. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1007\/s00018-009-9150-2","article-title":"Protein Kinase CK2 in Health and Disease","volume":"66","author":"Litchfield","year":"2009","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_18","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. Enzym. Regul."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.2174\/092986708785132933","article-title":"Protein Kinase CK2 in Human Diseases","volume":"15","author":"Guerra","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Chua, M.M., Ortega, E.C., Sheikh, A., Lee, M., Abdul-Rassoul, H., Hartshorn, L.K., and Dominguez, I. (2017). CK2 in Cancer: Cellular and Biochemical Mechanisms and Potential Therapeutic Target. Pharmaceuticals, 10.","DOI":"10.3390\/ph10010018"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"77","DOI":"10.2174\/1568009043481687","article-title":"Protein Kinase CK2 as Regulator of Cell Survival: Implications for Cancer Therapy","volume":"4","author":"Unger","year":"2004","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"671","DOI":"10.2174\/092986713804999312","article-title":"Kinase CK2 Inhibition: An Update","volume":"20","author":"Cozza","year":"2013","journal-title":"Curr. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3173","DOI":"10.1007\/s00018-013-1552-5","article-title":"Cell-permeable dual inhibitors of protein kinases CK2 and PIM-1: Structural features and pharmacological potential","volume":"71","author":"Cozza","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Cozza, G. (2017). The Development of CK2 Inhibitors: From Traditional Pharmacology to in Silico Rational Drug Design. Pharmaceuticals, 10.","DOI":"10.3390\/ph10010026"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1007\/s00018-009-9155-x","article-title":"Protein Kinase CK2 in Health and Disease","volume":"66","author":"Battistutta","year":"2009","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0163-7258(02)00185-7","article-title":"Toward the rational design of protein kinase casein kinase-2 inhibitors","volume":"93","author":"Sarno","year":"2002","journal-title":"Pharmacol. Therapeut."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1021\/cb3007133","article-title":"First Structure of Protein Kinase CK2 Catalytic Subunit with an Effective CK2\u03b2-Competitive Ligand","volume":"8","author":"Raaf","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.chembiol.2009.01.004","article-title":"New Protein Kinase CK2 Inhibitors: Jumping out of the Catalytic Box","volume":"16","author":"Prudent","year":"2009","journal-title":"Chem. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"72482","DOI":"10.1039\/C5RA12114K","article-title":"Synthesis, biological activity and structural study of new benzotriazole-based protein kinase CK2 inhibitors","volume":"5","author":"Swider","year":"2015","journal-title":"RSC Adv."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"66595","DOI":"10.1039\/C6RA09717K","article-title":"Design and synthesis of novel dual-target agents for HDAC1 and CK2 inhibition","volume":"6","author":"Purwin","year":"2016","journal-title":"RSC Adv."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1039\/C8OB02990C","article-title":"From a MMP2\/CK2 multitarget approach to the identification of potent and selective MMP13 inhibitors","volume":"17","author":"Pastor","year":"2019","journal-title":"Org. Biomol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: An N\u22c5log(N) method for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2920","DOI":"10.1016\/j.bmcl.2009.04.076","article-title":"Structural insight into human CK2alpha in complex with the potent inhibitor ellagic acid","volume":"19","author":"Sekiguchi","year":"2009","journal-title":"Bioorgan. Med. Chem. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1021\/jm101251q","article-title":"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","volume":"54","author":"Pierre","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"8478","DOI":"10.1021\/bi2008382","article-title":"Unprecedented Selectivity and Structural Determinants of a New Class of Protein Kinase CK2 Inhibitors in Clinical Trials for the Treatment of Cancer","volume":"50","author":"Battistutta","year":"2011","journal-title":"Biochemistry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.canlet.2008.08.016","article-title":"HDAC family: What are the cancer relevant targets?","volume":"277","author":"Witt","year":"2009","journal-title":"Cancer Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/35106079","article-title":"Histone deacetylases and cancer: Causes and therapies","volume":"1","author":"Marks","year":"2001","journal-title":"Nat. Rev. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1146\/annurev-pharmtox-011112-140216","article-title":"The Potential of HDAC Inhibitors as Cognitive Enhancers","volume":"53","author":"Tsai","year":"2013","journal-title":"Annu. Rev. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/icb.2011.97","article-title":"HDAC inhibitors in parasitic diseases","volume":"90","author":"Andrews","year":"2012","journal-title":"Immunol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"272","DOI":"10.2174\/156802609788085296","article-title":"Non-Cancer Uses of Histone Deacetylase Inhibitors: Effects on Infectious Diseases and \u03b2-Hemoglobinopathies+","volume":"9","author":"Rotili","year":"2009","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/nrendo.2009.102","article-title":"Epigenetic mechanisms that underpin metabolic and cardiovascular diseases","volume":"5","author":"Gluckman","year":"2009","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jmb.2004.02.006","article-title":"Molecular Evolution of the Histone Deacetylase Family: Functional Implications of Phylogenetic Analysis","volume":"338","author":"Gregoretti","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/nrg2485","article-title":"The many roles of histone deacetylases in development and physiology: Implications for disease and therapy","volume":"10","author":"Haberland","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0065-230X(02)86002-X","article-title":"Histone acetyltransferases and deacetylases in the control of cell proliferation and differentiation","volume":"86","author":"Lehrmann","year":"2002","journal-title":"Adv. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5459","DOI":"10.1200\/JCO.2009.22.1291","article-title":"Histone Deacetylase Inhibitors in Cancer Therapy","volume":"27","author":"Lane","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/nrc1779","article-title":"Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer","volume":"6","author":"Minucci","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/med.20200","article-title":"Histone deacetylase inhibitors (HDACIs). Structure\u2014Activity relationships: History and new QSAR perspectives","volume":"32","author":"Pontiki","year":"2012","journal-title":"Med. Res. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1021\/jm7011408","article-title":"Histone Deacetylase Inhibitors: From Bench to Clinic","volume":"51","author":"Paris","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"39","DOI":"10.2174\/1568009617666170206102613","article-title":"Multimodal HDAC Inhibitors with Improved Anticancer Activity","volume":"18","author":"Schobert","year":"2018","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1002\/med.21505","article-title":"Chimeric HDAC inhibitors: Comprehensive review on the HDAC-based strategies developed to combat cancer","volume":"38","author":"Hesham","year":"2018","journal-title":"Med. Res. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4550","DOI":"10.1021\/acs.jmedchem.5b00099","article-title":"Novel Bioactive Hybrid Compound Dual Targeting Estrogen Receptor and Histone Deacetylase for the Treatment of Breast Cancer","volume":"58","author":"Tang","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4325","DOI":"10.1021\/acs.jmedchem.5b00317","article-title":"Design, Synthesis, and Antitumor Evaluation of Novel Histone Deacetylase Inhibitors Equipped with a Phenylsulfonylfuroxan Module as a Nitric Oxide Donor","volume":"58","author":"Duan","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"475","DOI":"10.2174\/092986712798918842","article-title":"Multi-Targeted Histone Deacetylase Inhibitors in Cancer Therapy","volume":"19","author":"Ai","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s12272-012-0221-9","article-title":"Multi-targeted hybrids based on HDAC inhibitors for anti-cancer drug discovery","volume":"35","author":"Seo","year":"2012","journal-title":"Arch. Pharm. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1021\/jm200799p","article-title":"Dual Targeting of Histone Deacetylase and Topoisomerase II with Novel Bifunctional Inhibitors","volume":"55","author":"Guerrant","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5950","DOI":"10.1016\/j.bmc.2010.06.081","article-title":"Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylase based on a cinnamic hydroxamic acid core structure","volume":"18","author":"Chen","year":"2010","journal-title":"Bioorgan. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"8250","DOI":"10.1073\/pnas.0709279105","article-title":"Incorporation of histone deacetylase inhibition into the structure of a nuclear receptor agonist","volume":"105","author":"Quach","year":"2008","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4869","DOI":"10.1021\/acs.jmedchem.6b01862","article-title":"Design and Discovery of N-(2-Methyl-5\u2032-morpholino-6\u2032-((tetrahydro-2H-pyran-4-yl)oxy)-[3\u2032,-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers","volume":"60","author":"Nishiguchi","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/0929867327666200102115720","article-title":"Recent Advances in Multi-target Drugs Targeting Protein Kinases and Histone Deacetylases in Cancer Therapy","volume":"27","author":"Ling","year":"2020","journal-title":"Curr. Med. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.ejmech.2018.09.024","article-title":"Design and synthesis of potent dual inhibitors of JAK2 and HDAC based on fusing the pharmacophores of XL019 and vorinostat","volume":"158","author":"Mustafa","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3171","DOI":"10.1021\/acs.jmedchem.8b00189","article-title":"Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer Therapy","volume":"62","author":"Luan","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1021\/jm901453q","article-title":"Discovery of 7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a Potent Multi-Acting HDAC, EGFR, and HER2 Inhibitor for the Treatment of Cancer","volume":"53","author":"Cai","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1021\/jm800988r","article-title":"Design of Chimeric Histone Deacetylase- and Tyrosine Kinase-Inhibitors: A Series of Imatinib Hybrides as Potent Inhibitors of Wild-Type and Mutant BCR-ABL, PDGF-R\u03b2, and Histone Deacetylases","volume":"52","author":"Mahboobi","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"16518","DOI":"10.1074\/jbc.M112.440446","article-title":"Protein kinase CK2 regulates the dimerization of histone deacetylase 1 (HDAC1) and HDAC2 during mitosis","volume":"288","author":"Khan","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/ijc.23094","article-title":"Protein kinase CK2 is a key activator of histone deacetylase in hypoxia-associated tumors","volume":"122","author":"Pluemsampant","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4905","DOI":"10.1021\/cr200409f","article-title":"Click Chemistry for Drug Development and Diverse Chemical\u2013Biology Applications","volume":"113","author":"Thirumurugan","year":"2013","journal-title":"Chem. Rev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1016\/S0968-0896(03)00403-6","article-title":"Polyhalogenobenzimida-zoles: Synthesis and Their inhibitory activity against casein kinases","volume":"11","author":"Andrzejewska","year":"2003","journal-title":"Bioorgan. Med. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s11010-011-0962-7","article-title":"Multisite-directed inhibitors of protein kinase CK2: New challenges","volume":"356","author":"Ramos","year":"2011","journal-title":"Mol. Cell. Biochem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"8054","DOI":"10.1021\/acs.jmedchem.8b01013","article-title":"Histone Deacetylase 6-Selective Inhibitors and the Influence of Capping Groups on Hydroxamate-Zinc Denticity","volume":"61","author":"Porter","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"6503","DOI":"10.2147\/IJN.S136142","article-title":"Combination of palladium nanoparticles and tubastatin-A potentiates apoptosis in human breast cancer cells: A novel therapeutic approach for cancer","volume":"12","author":"Yuan","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3454","DOI":"10.1021\/acs.jmedchem.7b01593","article-title":"Marbostat-100 Defines a New Class of Potent and Selective Antiinflammatory and Antirheumatic Histone Deacetylase 6 Inhibitors","volume":"61","author":"Sellmer","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6056","DOI":"10.1021\/acs.jmedchem.8b00393","article-title":"Discovery of Janus Kinase 2 (JAK2) and Histone Deacetylase (HDAC) Dual Inhibitors as a Novel Strategy for the Combinational Treatment of Leukemia and Invasive Fungal Infections","volume":"61","author":"Huang","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4395","DOI":"10.1021\/ja01573a042","article-title":"Halogenated benzotriazoles","volume":"79","author":"Wiley","year":"1957","journal-title":"J. Am. Chem. Soc."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6239","DOI":"10.1021\/jm049854a","article-title":"Optimization of Protein Kinase CK2 Inhibitors Derived from 4,5,6,7-Tetrabromobenzimidazole","volume":"47","author":"Pagano","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1110\/ps.19601","article-title":"Structural features underlying selective inhibition of protein kinase CK2 by ATP site-directed tetrabromo-2-benzotriazole","volume":"10","author":"Battistutta","year":"2001","journal-title":"Protein Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1002\/cbic.200700307","article-title":"The ATP-Binding Site of Protein Kinase CK2 Holds a Positive Electrostatic Area and Conserved Water Molecules","volume":"8","author":"Battistutta","year":"2007","journal-title":"Chembiochem"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1016\/j.chembiol.2005.08.015","article-title":"Inspecting the structure-activity relationship of protein kinase CK2 inhibitors derived from tetrabromo-benzimidazole","volume":"12","author":"Battistutta","year":"2005","journal-title":"Chem. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"77254","DOI":"10.18632\/oncotarget.20460","article-title":"Histone deacetylase inhibitors vorinostat and panobinostat induce G1 cell cycle arrest and apoptosis in multidrug resistant sarcoma cell lines","volume":"8","author":"Bernhart","year":"2017","journal-title":"Oncotarget"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1158\/2159-8290.CD-12-0012","article-title":"Circumventing Cancer Drug Resistance in the Era of Personalized Medicine","volume":"2","author":"Garraway","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1186\/s13046-019-1292-y","article-title":"Role of protein kinase CK2 in antitumor drug resistance","volume":"38","author":"Borgo","year":"2019","journal-title":"J. Exp. Clin. Canc. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"6544","DOI":"10.18632\/oncotarget.3446","article-title":"Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth","volume":"6","author":"Pizzi","year":"2015","journal-title":"Oncotarget"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1016\/j.bcp.2007.08.026","article-title":"Mechanisms underlying the anticancer activities of the angucycline landomycin E","volume":"74","author":"Korynevska","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Ruiz-Ojeda, F.J., Gomez-Llorente, C., Aguilera, C.M., Gil, A., and Rup\u00e9rez, A.I. (2016). Impact of 3-Amino-1,2,4-Triazole (3-AT)-Derived Increase in Hydrogen Peroxide Levels on Inflammation and Metabolism in Human Differentiated Adipocytes. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0152550"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"11262","DOI":"10.1038\/ncomms11262","article-title":"Insights into the activation mechanism of class I HDAC complexes by inositol phosphates","volume":"7","author":"Watson","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nchembio.2134","article-title":"Histone deacetylase 6 structure and molecular basis of catalysis and inhibition","volume":"12","author":"Hai","year":"2016","journal-title":"Nat. Chem. Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"11636","DOI":"10.1021\/ja501548p","article-title":"Inhibition and Mechanism of HDAC8 Revisited","volume":"136","author":"Chen","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments","volume":"27","author":"Sastry","year":"2013","journal-title":"J. Comput. Aid. Mol. Des."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra Precision Glide:\u2009 Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein\u2212Ligand Complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_90","unstructured":"Case, D.A., Betz, R.M., Cerutti, D.S., Cheatham, T.E., Darden, T.A., Duke, R.E., Giese, T.J., Gohlke, H., Goetz, A.W., and Homeyer, N. (2016). AMBER 2016, University of California."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1021\/acs.jcim.5b00674","article-title":"MCPB.py: A Python Based Metal Center Parameter Builder","volume":"56","author":"Li","year":"2016","journal-title":"J. Chem. Inf. Model."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1002\/bab.1583","article-title":"Molecular dynamics study on the Apo- and Holo-forms of 5-lipoxygenase","volume":"65","author":"Torras","year":"2018","journal-title":"Biotechnol. Appl. Bioc."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","article-title":"ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB","volume":"11","author":"Maier","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1080\/08927029408022001","article-title":"A Non-Iterative Matrix Method for Constraint Molecular Dynamics Simulations","volume":"13","author":"Yoneya","year":"1994","journal-title":"Mol. Simulat."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4193","DOI":"10.1021\/ja00119a045","article-title":"Molecular Dynamics Simulations on Solvated Biomolecular Systems: The Particle Mesh Ewald Method Leads to Stable Trajectories of DNA, RNA, and Proteins","volume":"117","author":"Cheatham","year":"1995","journal-title":"J. Am. Chem. Soc."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1021\/ct400341p","article-title":"PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data","volume":"9","author":"Roe","year":"2013","journal-title":"J. Chem Theory Comput."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1006\/excr.1993.1173","article-title":"Relationship between Apoptosis and the Cell Cycle in Lymphocytes: Roles of Protein Kinase C, Tyrosine Phosphorylation, and AP1","volume":"207","author":"Walker","year":"1993","journal-title":"Exp. Cell Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/7\/1497\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:11:34Z","timestamp":1760173894000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/7\/1497"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,25]]},"references-count":97,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["molecules25071497"],"URL":"https:\/\/doi.org\/10.3390\/molecules25071497","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,25]]}}}