Kluge Arthur F, Lagu Bharat R, Maiti Pranab, Jaleel Mahaboobi, Webb Michael, Malhotra Jyoti, Mallat Ashley, Srinivas P Akhila, Thompson James E
Mitobridge, Inc. (an Astellas company), 1030 Massachusetts Avenue, Cambridge, MA 02138, United States.
Mitobridge, Inc. (an Astellas company), 1030 Massachusetts Avenue, Cambridge, MA 02138, United States.
Bioorg Med Chem Lett. 2018 Aug 15;28(15):2655-2659. doi: 10.1016/j.bmcl.2018.05.013. Epub 2018 May 8.
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.
线粒体自噬是细胞用于维持整体健康的过程之一。一种E3连接酶——帕金蛋白，会在自噬体降解线粒体蛋白之前使其泛素化。USP30是一种使线粒体蛋白去泛素化的酶；因此，抑制这种酶可以促进线粒体自噬。在此，我们揭示了一系列新型高选择性USP30抑制剂的构效关系（SAR）。两种结构相似的化合物，MF - 094（一种强效且选择性的USP30抑制剂）和MF - 095（一种效力明显较低的USP30抑制剂），可作为生物学评估的有用对照。我们表明，MF - 094可增加蛋白质泛素化并加速线粒体自噬。
