Multicomponent Synthesis, Binding Mode, and Structure–Activity Relationship of Selective Histone Deacetylase 6 (HDAC6) Inhibitors with Bifurcated Capping Groups
Autor: | David W. Christianson, Finn K. Hansen, Andrea Schöler, Alexander Jan Skerhut, Julian Schliehe-Diecks, Sanil Bhatia, Melf Sönnichsen, Arndt Borkhardt, Matthias U. Kassack, Julia Hauer, Jeremy D. Osko, Nina Reßing |
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Rok vydání: | 2020 |
Předmět: |
Daunorubicin
Tetrazoles Antineoplastic Agents Plasma protein binding Histone Deacetylase 6 01 natural sciences Article Bortezomib Structure-Activity Relationship 03 medical and health sciences Cell Line Tumor Drug Discovery medicine Animals Humans Structure–activity relationship Cytotoxicity Epirubicin 030304 developmental biology chemistry.chemical_classification 0303 health sciences Molecular Structure Drug Synergism HDAC6 3. Good health 0104 chemical sciences Histone Deacetylase Inhibitors 010404 medicinal & biomolecular chemistry Enzyme chemistry Microsomes Liver Proteasome inhibitor Cancer research Molecular Medicine Drug Screening Assays Antitumor Protein Binding medicine.drug |
Zdroj: | J Med Chem Journal of Medicanial Chemistry |
ISSN: | 1520-4804 0022-2623 |
DOI: | 10.1021/acs.jmedchem.9b01888 |
Popis: | Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by investigating the inhibition of recombinant HDAC enzymes and protein acetylation. A cocrystal structure of HDAC6 complexed with NR-160 disclosed that the steric complementarity of the bifurcated capping group of NR-160 to the L1 and L2 loop pockets may be responsible for its HDAC6-selective inhibition. While NR-160 displayed only low cytotoxicity as a single agent against leukemia cell lines, it augmented the apoptosis induction of the proteasome inhibitor bortezomib in combination experiments significantly. Furthermore, a combinatorial high-throughput drug screen revealed significantly enhanced cytotoxicity when NR-160 was used in combination with epirubicin and daunorubicin. The synergistic effect in combination with bortezomib and anthracyclines highlights the potential of NR-160 in combination therapies. |
Databáze: | OpenAIRE |
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