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SHR Neuro Cancer Cardio Lipid Metab Microb

Martínez, R; Geronimo, BD; Pastor, M; Zapico, JM; 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(7): Doi: 10.3390/molecules25071497 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

Co-authors Med Uni Graz: Di Geronimo Quintero Bruno
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Abstract:: 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.
Find related publications in this database (using NLM MeSH Indexing): Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Casein Kinase II - analysis, antagonists & inhibitors; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor - administration & dosage; Drug Resistance, Neoplasm - drug effects; Histone Deacetylase Inhibitors - chemical synthesis, chemistry, pharmacology; Humans - administration & dosage; Protein Kinase Inhibitors - chemical synthesis, chemistry, pharmacology; Reactive Oxygen Species - metabolism
Find related publications in this database (Keywords): HDAC; CK2; multi-target inhibitors; docking; molecular dynamics; CuAAC; cytotoxic activity