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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred


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Kinetically selective and potent inhibitors of HDAC8

Markus Schweipert
  • Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Stephanstr. 7, 64295 Darmstadt, Germany
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/ Niklas Jänsch
  • Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Stephanstr. 7, 64295 Darmstadt, Germany
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/ Wisely Oki Sugiarto
  • Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Stephanstr. 7, 64295 Darmstadt, Germany
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/ Franz-Josef Meyer-Almes
  • Corresponding author
  • Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Stephanstr. 7, 64295 Darmstadt, Germany
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Published Online: 2018-12-22 | DOI: https://doi.org/10.1515/hsz-2018-0363

Abstract

Histone deacetylase 8 (HDAC8) is an established and validated target for T-cell lymphoma and childhood neuroblastoma. The active site binding pocket of HDAC8 is highly conserved among all zinc-containing representatives of the histone deacetylase (HDAC) family. This explains that most HDACs are unselectively recognized by similar inhibitors featuring a zinc binding group (ZBG), a hydrophobic linker and a head group. In the light of this difficulty, the creation of isoenzyme-selectivity is one of the major challenges in the development of HDAC inhibitors. In a series of trifluoromethylketone inhibitors of HDAC8 compound 10 shows a distinct binding mechanism and a dramatically increased residence time (RT) providing kinetic selectivity against HDAC4. Combining the binding kinetics results with computational docking and binding site flexibility analysis suggests that 10 occupies the conserved catalytic site as well as an adjacent transient sub-pocket of HDAC8.

This article offers supplementary material which is provided at the end of the article.

Keywords: histone deacetylase; residence time; transient binding pocket

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About the article

Received: 2018-08-31

Accepted: 2018-11-25

Published Online: 2018-12-22


Citation Information: Biological Chemistry, 20180363, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2018-0363.

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