Novel highly selective inhibitors of ubiquitin specific protease 30 (USP30) accelerate mitophagy
Novel highly selective inhibitors of ubiquitin specific protease 30 (USP30) accelerate mitophagy
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DOI：
10.1016/j.bmcl.2018.05.013
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发表时间：
2018-08-15
影响因子：
2.7
通讯作者：
Thompson, James E.
中科院分区：
文献类型：
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作者：
Kluge, Arthur F.;Lagu, Bharat R.;Thompson, James E.
线粒体自噬是细胞用来维持整体健康的过程之一。E3连接酶parkin在线粒体蛋白被自噬体降解之前将其泛素化。USP 30是一种去泛素化线粒体蛋白的酶;因此，抑制这种酶可以促进线粒体自噬。在此，我们公开了一系列新型高选择性USP 30抑制剂的结构-活性关系（SAR）。两种结构相似的化合物MF-094（一种强效和选择性USP 30抑制剂）和MF-095（一种效力显著较低的USP 30抑制剂）可用作生物学评价的有效对照。我们发现MF-094增加蛋白质泛素化并加速线粒体自噬。(C)2018爱思唯尔有限公司版权所有
Mitophagy is one of the processes that cells use to maintain overall health. An E3 ligase, parkin, ubiquitinates mitochondrial proteins prior to their degradation by autophagasomes. USP30 is an enzyme that de-ubiquitinates mitochondrial proteins; therefore, inhibiting this enzyme could foster mitophagy. Herein, we disclose the structure-activity relationships (SAR) within a novel series of highly selective USP30 inhibitors. Two structurally similar compounds, MF-094 (a potent and selective USP30 inhibitor) and MF-095 (a significantly less potent USP30 inhibitor), serve as useful controls for biological evaluation. We show that MF-094 increases protein ubiquitination and accelerates mitophagy. (C) 2018 Elsevier Ltd. All rights reserved.