Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 164, Issue -, Pages 263-272Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.12.056
Keywords
Histone deacetylases 6; Cancer; Neurodegenerative diseases; Drug addiction
Categories
Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [NRF-2016R1A6A1A03011325, 2016R1D1A1B01009559]
- Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries (IPET) through Animal Disease Management Technology Development Program - Ministry of Agriculture, Food and Rural Affairs (MAFRA) [116102-03]
- National Research Foundation of Korea [2016R1D1A1B01009559] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Histone deacetylase 6 (HDAC6) is an important target for the treatment of diverse diseases including cancer, neurodegenerative diseases, autoimmune disorders, inflammation, drug addiction, and viral infection. Therefore, the discovery of HDAC6-isoform selective inhibitors is of high importance for clinical applications. Here, we present an approach to discover HDAC6-isoform selective inhibitors. To our best knowledge, we for the first time perform a virtual screening campaign in the surface and channel region of HDAC6 enzyme, followed by rational installation of zinc binding group for the development of HDAC6-isoform selective inhibitors. Consequently, this approach establishes the proof of principle for the discovery of HDAC6-isoform selective inhibitors and successfully provides our lead compound 3. In particular, compound 3 inhibits HDAC6 enzyme with an IC50 value of 56 nM and displays an excellent HDAC6 selectivity over other HDAC isoforms in HDAC enzyme assay. Furthermore, the exposure of SH-SY5Y cells with compound 3 significantly promotes the acetylation of alpha-tubulin at the low concentration of 0.5 mu M, but not the acetylation of Histone H3 up to 20 mu M. Thus, our lead compound 3 represents a novel HDAC6-isoform selective inhibitor and warrants further studies for therapeutic evaluation. (C) 2018 Elsevier Masson SAS. All rights reserved.
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