2. Academic Validation
  3. Discovery of small-molecule positive allosteric modulators of Parkin E3 ligase

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

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.

Figures
Products