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Open AccessFeature PaperArticle

Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 inhibitors

1
Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925 Alcorcón, Madrid, Spain
2
Institute of Cell Biology, NAS of Ukraine, Drahomanov Str. 14/16, 79005 Lviv, Ukraine
3
Department of Molecular Biology, Faculty of Biotechnology and Environment Sciences, The John Paul II Catholic University of Lublin, 20-718 Lublin, Poland
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(7), 1497; https://doi.org/10.3390/molecules25071497 (registering DOI)
Received: 28 February 2020 / Revised: 21 March 2020 / Accepted: 23 March 2020 / Published: 25 March 2020
(This article belongs to the Special Issue Design, Synthesis, and Biological Evaluation of Enzyme Inhibitors)
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 µM. 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.
Keywords: HDAC; CK2; multi-target inhibitors; docking; molecular dynamics; CuAAC; cytotoxic activity HDAC; CK2; multi-target inhibitors; docking; molecular dynamics; CuAAC; cytotoxic activity
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MDPI and ACS Style

Martínez, R.; Geronimo, B.D.; Pastor, M.; Zapico, J.M.; Coderch, C.; Panchuk, R.; Skorokhyd, N.; Maslyk, M.; Ramos, A.; de Pascual-Teresa, B. Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 inhibitors. Molecules 2020, 25, 1497.

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