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Licensed Unlicensed Requires Authentication Published by De Gruyter December 22, 2018

Kinetically selective and potent inhibitors of HDAC8

  • Markus Schweipert , Niklas Jänsch , Wisely Oki Sugiarto and Franz-Josef Meyer-Almes EMAIL logo
From the journal Biological Chemistry

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.

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2018-0363).


Received: 2018-08-31
Accepted: 2018-11-25
Published Online: 2018-12-22
Published in Print: 2019-06-26

©2019 Walter de Gruyter GmbH, Berlin/Boston

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