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

Evgeny Shlevkov; Paramasivam Murugan; Dan Montagna; Eric Stefan; Adelajda Hadzipasic; James S Harvey; P Rajesh Kumar; Sonya Entova; Nupur Bansal; Shari Bickford; Lai-Yee Wong; Warren D Hirst; Andreas Weihofen; Laura F Silvian

doi:10.1016/j.isci.2021.103650

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. eCollection 2022 Jan 21.

Affiliations

¹ Neurodegenerative Disease Research Unit, Biogen, Cambridge, MA 02142, USA.
² Biotherapeutics and Medicinal Sciences, 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.

Keywords: Biochemistry; Biochemistry Applications; Chemistry.