Design and evaluation of 'Linkerless' hydroxamic acids as selective HDAC8 inhibitors
Design and evaluation of 'Linkerless' hydroxamic acids as selective HDAC8 inhibitors
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DOI：
10.1016/j.bmcl.2007.02.064
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发表时间：
2007-05-15
影响因子：
2.7
通讯作者：
Ulrich, Scott M.
中科院分区：
文献类型：
--
作者：
KrennHrubec, Keris;Marshall, Brett L.;Ulrich, Scott M.
在这份报告中，我们描述了新的HDAC抑制剂，旨在利用一个独特的子口袋中的HDAC 8活性位点。这些化合物是基于对与各种抑制剂结合的可用HDAC 8晶体结构的检查，其共同显示HDAC 8活性位点具有异常的延展性，并且可以容纳与SAHA、TSA和类似HDAC抑制剂的典型“锌结合基团-接头-帽基团”结构不同的抑制剂结构。基于这种新支架的一些抑制剂对HDAC 8的选择性是其他I类和II类HDAC的100倍以上，针对HDAC 8的IC 50值< 1 μ M。此外，与广谱HDAC抑制剂TSA相比，用本文所述的抑制剂处理人细胞显示出独特的超乙酰化蛋白质模式。(c)2007爱思唯尔有限公司保留所有权利。
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 IC50 values < 1 mu M 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. (c) 2007 Elsevier Ltd. All rights reserved.