Discovery of small-molecule positive allosteric modulators of Parkin E3 ligase
Evgeny Shlevkov1, Paramasivam Murugan2, Dan Montagna1
1Neurodegenerative Disease Research Unit, Biogen, Cambridge, MA 02142, USA.
Abstract:
Pharmacological activation of the E3 ligase Parkin represents a rational therapeutic intervention for the treatment of Parkinson's disease. Here we 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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