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

  • iScience. 2021 Dec 18;25(1):103650. doi: 10.1016/j.isci.2021.103650.
Evgeny Shlevkov  1 ,  Paramasivam Murugan  2 ,  Dan Montagna  1 ,  Eric Stefan  2 ,  Adelajda Hadzipasic  2 ,  James S Harvey  2 ,  P Rajesh Kumar  2 ,  Sonya Entova  2 ,  Nupur Bansal  2 ,  Shari Bickford  2 ,  Lai-Yee Wong  2 ,  Warren D Hirst  1 ,  Andreas Weihofen  1 ,  Laura F Silvian  2
Affiliations
  • 1. Neurodegenerative Disease Research Unit, Biogen, Cambridge, MA 02142, USA.
  • 2. Biotherapeutics and Medicinal Sciences, Biogen, Cambridge, MA 02142, USA.
PMID: 35024585 DOI: 10.1016/j.isci.2021.103650
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.

Keywords
Biochemistry; Biochemistry Applications; Chemistry.
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