Correlation between chemotype-dependent binding conformations of HSP90α/β and isoform selectivity-Implications for the structure-based design of HSP90α/β selective inhibitors for treating neurodegenerative diseases
Correlation between chemotype-dependent binding conformations of HSP90α/β and isoform selectivity-Implications for the structure-based design of HSP90α/β selective inhibitors for treating neurodegenerative diseases
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DOI：
10.1016/j.bmcl.2013.11.036
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发表时间：
2014-01-01
影响因子：
2.7
通讯作者：
Stamos, Dean
中科院分区：
文献类型：
--
作者：
Ernst, Justin T.;Liu, Michael;Stamos, Dean
HSP 90仍然是神经变性适应症的目标。HSP 90胞质异构体α和β的选择性敲低足以降低体外突变亨廷顿蛋白水平。HSP 90 α/β的化学型依赖性结合构象似乎强烈影响异构体选择性。相对于线粒体（TRAP 1）和内质网（GRP 94）亚型的选择性HSP 90 α/β抑制剂的合理设计为基于机制的毒性提供了潜在的缓解策略。耐受性更好的HSP 90抑制剂对于靶向慢性神经退行性疾病如亨廷顿病将是有吸引力的。(C)2013爱思唯尔有限公司保留所有权利。
HSP90 continues to be a target of interest for neurodegeneration indications. Selective knockdown of the HSP90 cytosolic isoforms alpha and beta is sufficient to reduce mutant huntingtin protein levels in vitro. Chemotype-dependent binding conformations of HSP90 alpha/beta appear to strongly influence isoform selectivity. The rational design of HSP90 alpha/beta inhibitors selective versus the mitochondrial (TRAP1) and endoplasmic reticulum (GRP94) isoforms offers a potential mitigating strategy for mechanism-based toxicities. Better tolerated HSP90 inhibitors would be attractive for targeting chronic neurodegenerative diseases such as Huntington's disease. (C) 2013 Elsevier Ltd. All rights reserved.