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Structure-based design and biological characterization of selective histone deacetylase 8 (HDAC8) inhibitors with anti-neuroblastoma activity

Histone deacetylases (HDACs) are important modulators of epigenetic gene regulation and additionally control the activity of non-histone protein substrates. While for HDACs 1-3 and 6 many potent selective inhibitors have been obtained, for other subtypes much less is known on selective inhibitors an...

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Bibliographic Details
Main Authors: Heimburg, Tino (Author) , Witt, Olaf (Author)
Format: Article (Journal)
Language:English
Published: November 30, 2017
In: Journal of medicinal chemistry
Year: 2017, Volume: 60, Issue: 24, Pages: 10188-10204
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.7b01447
Online Access:Verlag, kostenfrei registrierungspflichtig, Volltext: http://dx.doi.org/10.1021/acs.jmedchem.7b01447
Verlag, kostenfrei registrierungspflichtig, Volltext: https://doi.org/10.1021/acs.jmedchem.7b01447
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Author Notes:Tino Heimburg, Fiona R. Kolbinger, Patrik Zeyen, Ehab Ghazy, Daniel Herp, Karin Schmidtkunz, Jelena Melesina, Tajith Baba Shaik, Frank Erdmann, Matthias Schmidt, Christophe Romier, Dina Robaa, Olaf Witt, Ina Oehme, Manfred Jung, and Wolfgang Sippl
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Summary:Histone deacetylases (HDACs) are important modulators of epigenetic gene regulation and additionally control the activity of non-histone protein substrates. While for HDACs 1-3 and 6 many potent selective inhibitors have been obtained, for other subtypes much less is known on selective inhibitors and the consequences of their inhibition. The present report describes the development of substituted benzhydroxamic acids as potent and selective HDAC8 inhibitors. Docking studies using available crystal structures have been used for structure-based optimization of this series of compounds. Within this study, we have investigated the role of HDAC8 in the proliferation of cancer cells and optimized hits for potency and selectivity, both in vitro and in cell culture. The combination of structure-based design, synthesis, and in vitro screening to cellular testing resulted in potent and selective HDAC8 inhibitors that showed anti-neuroblastoma activity in cellular testing.
Item Description:Gesehen am 17.04.2018
Physical Description:Online Resource
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.7b01447

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