Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7.
Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7.
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DOI：
10.1016/j.chembiol.2017.09.003
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发表时间：
2017-12-21
影响因子：
8.6
通讯作者：
Buhrlage SJ
中科院分区：
文献类型：
--
作者：
Lamberto I;Liu X;Seo HS;Schauer NJ;Iacob RE;Hu W;Das D;Mikhailova T;Weisberg EL;Engen JR;Anderson KC;Chauhan D;Dhe-Paganon S;Buhrlage SJ
去泛素化酶（DUBs）作为药物靶点在过去5-10年中获得了显著的关注。这种兴奋在很大程度上源于DUB抑制剂促进致癌蛋白降解的强大能力，特别是那些难以直接靶向但被DUB家族成员稳定的蛋白。因此，高度优化和充分表征的DUB抑制剂已成为备受追捧的工具。然而，大多数报道的DUB抑制剂是对它们的主要靶点具有弱（微摩尔）效力的多药理学试剂，限制了它们在靶点验证和机制研究中的效用。由于缺乏高分辨率的DUB·小分子配体复合物结构，尚未报道针对哺乳动物DUB的结构指导优化工作。在这里，我们报告了一个小分子·泛素特异性蛋白酶（USP）家族DUB的共结构和快速设计的有效和选择性的抑制剂的USP 7的结构指导。有趣的是，这些化合物是非共价活性位点抑制剂。Lamberto等人报告了去泛素化酶（DUB）抑制剂的结构指导开发USP 7。这些研究为研究正常和疾病生物学中的USP 7提供了优化和充分表征的探针，此外，还验证了可以实现DUB的有效和选择性活性位点抑制剂的概念。
Deubiquitinating enzymes (DUBs) have garnered significant attention as drug targets in the last 5–10 years. The excitement stems in large part from the powerful ability of DUB inhibitors to promote degradation of oncogenic proteins, especially proteins that are challenging to directly target but which are stabilized by DUB family members. Highly-optimized and well-characterized DUB inhibitors have thus become highly sought after tools. Most reported DUB inhibitors, however, are polypharmacological agents possessing weak (micromolar) potency toward their primary target, limiting their utility in target validation and mechanism studies. Due to a lack of high resolution DUB•small molecule ligand complex structures, no structure-guided optimization efforts have been reported for a mammalian DUB. Here, we report a small molecule•ubiquitin specific protease (USP) family DUB co-structure and rapid design of potent and selective inhibitors of USP7 guided by the structure. Interestingly, the compounds are noncovalent active site inhibitors. Lamberto, et al. report the structure-guided development of inhibitors of the deubiquitinating enzyme (DUB) USP7. The studies provide optimized and well-characterized probes for studying USP7 in normal and disease biology and furthermore, lend validation to the notion that potent and selective active site inhibitors of DUBs can be achieved.
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影响因子：
3.5
作者：
Atanassov BS;Koutelou E;Dent SY
通讯作者：
Dent SY
DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
影响因子：
64.5
作者：
Cohen, Philip;Tcherpakov, Marianna
通讯作者：
Tcherpakov, Marianna
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
新型USP7抑制剂噻唑衍生物的合成及生物学评价
影响因子：
2.7
作者：
Chen, Chao;Song, Jiemei;Wen, Xiaoan
通讯作者：
Wen, Xiaoan