On the inhibition of histone deacetylase 8.
On the inhibition of histone deacetylase 8.
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DOI：
10.1016/j.bmc.2010.03.080
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发表时间：
2010-06-01
影响因子：
3.5
通讯作者：
Wiest, Olaf
中科院分区：
文献类型：
--
作者：
Estiu, Guillermina;West, Nathan;Mazitschek, Ralph;Greenberg, Edward;Bradner, James E.;Wiest, Olaf
组蛋白去乙酰化酶是基因表达的关键调节因子，最近已成为癌症和越来越多的非恶性疾病的重要治疗靶点。许多广泛研究的HDAC抑制剂如SAHA被认为在人HDAC同种型类别内或之间具有低选择性。使用异构体选择性测定，我们已经表明，许多已知的抑制剂实际上对HDAC 8具有低活性。基于丰富的结构信息可用于人类HDAC8，我们使用对接和分子动力学模拟相结合，以确定实验结果的结构起源。发现HDAC 8的活性与高表面延展性之间存在密切关系。这些结果为最近描述的“无接头”HDAC 8选择性抑制剂和HDAC 8选择性抑制剂的设计标准提供了理论基础。
Histone deacetylases are key regulators of gene expression and have recently emerged as important therapeutic targets for cancer and a growing number of non-malignant diseases. Many widely studied inhibitors of HDACs such as SAHA are thought to have low selectivity within or between the human HDAC isoform classes. Using an isoform-selective assay, we have shown that a number of the known inhibitors have in fact a low activity against HDAC8. Based on the wealth of structural information available for human HDAC8, we use a combination of docking and molecular dynamics simulations to determine the structural origin of the experimental results. A close relationship is found between the activity and the high surface malleability of HDAC8. These results provide a rationale for the recently described “linkerless” HDAC8 selective inhibitors and design criteria for HDAC8 selective inhibitors.
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影响因子：
64.5
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
通讯作者：
Yao, TP
影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
通讯作者：
Mazitschek, Ralph
影响因子：
2.7
作者：
KrennHrubec, Keris;Marshall, Brett L.;Ulrich, Scott M.
通讯作者：
Ulrich, Scott M.
影响因子：
64.8
作者：
Finnin, MS;Donigian, JR;Pavletich, NP
通讯作者：
Pavletich, NP
影响因子：
5.6
作者：
Gregoretti, IV;Lee, YM;Goodson, HV
通讯作者：
Goodson, HV