Title

Design and evaluation of 'Linkerless' hydroxamic acids as selective HDAC8 inhibitors

Document Type

Article

Publication Date

5-15-2007

Abstract

In this report, we describe new HDAC inhibitors designed to exploit a unique sub-pocket in the HDAC8 active site. These compounds were based on inspection of the available HDAC8 crystal structures bound to various inhibitors, which collectively show that the HDAC8 active site is unusually malleable and can accommodate inhibitor structures that are distinct from the canonical 'zinc binding group-linker-cap group' structures of SAHA, TSA, and similar HDAC inhibitors. Some inhibitors based on this new scaffold are >100-fold selective for HDAC8 over other class I and class II HDACs with IC values <1 μM against HDAC8. Furthermore, treatment of human cells with the inhibitors described here shows a unique pattern of hyperacetylated proteins compared with the broad-spectrum HDAC inhibitor TSA. © 2007 Elsevier Ltd. All rights reserved. 50

Publication Name

Bioorganic and Medicinal Chemistry Letters

Volume Number

17

First Page

2874

Last Page

2878

Issue Number

10

DOI

10.1016/j.bmcl.2007.02.064

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