Discovery of small-molecule positive allosteric modulators of Parkin E3 ligase
Evgeny Shlevkov, Paramasivam Murugan, Dan Montagna, Eric Stefan, Adelajda Hadzipasic, James Harvey, P. Rajesh Kumar, Sonya Entova, Nupur Bansal, Shari Bickford, Lai-Yee Wong, Warren D. Hirst, Andreas Weihofen, Laura Silvian
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.