Discovery of small-molecule positive allosteric modulators of Parkin E3 ligase

被引：15
|
作者：
Shlevkov, Evgeny [2 ]
Murugan, Paramasivam [1 ]
Montagna, Dan [2 ]
Stefan, Eric [1 ]
Hadzipasic, Adelajda [1 ]
Harvey, James S. [1 ]
Kumar, P. Rajesh [1 ]
Entova, Sonya [1 ]
Bansal, Nupur [1 ]
Bickford, Shari [1 ]
Wong, Lai-Yee [1 ]
Hirst, Warren D. [2 ]
Weihofen, Andreas [2 ]
Silvian, Laura F. [1 ]
机构：
[1] Biogen, Biotherapeut & Med Sci, Cambridge, MA 02142 USA
[2] Biogen, Neurodegenerat Dis Res Unit, Cambridge, MA 02142 USA
来源：
ISCIENCE | 2022年 / 25卷 / 01期
关键词：
UBIQUITIN; PINK1; MUTATIONS; PHOSPHORYLATION; DISEASE; ACTIVATION; MECHANISM; PROBES; MIRO;
D O I：
10.1016/j.isci.2021.103650
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
Pharmacological activation of the E3 ligase Parkin represents a rational therapeutic intervention for the treatment of Parkinson's disease. Herewe identify several compounds that enhance the activity of wildtype Parkin in the presence of phospho-ubiquitin and act as positive allosteric modulators (PAMs). While these compounds activate Parkin in a series of biochemical assays, they do not act by thermally destabilizing Parkin and fail to enhance the Parkin translocation rate to mitochondria or to enact mitophagy in cell-based assays. We conclude that in the context of the cellular milieu the therapeutic window to pharmacologically activate Parkin is very narrow.
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页数：39
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