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Inhibitors of USP30 for the treatment of Parkinson’s disease and other mitochondrial dysfunctions


Parkinson’s disease (PD) affects around 10 million people worldwide (Parkinson’s Disease Foundation) and is characterised by the loss of dopaminergic neurons in the substantia nigra. The exact mechanisms underlying PD are unclear, however, mitochondrial dysfunction is thought to be a key factor. While most cases are linked to defects in alpha-synuclein, 10% of Parkinson’s cases are linked to specific genetic defects, one of which is in the ubiquitin E3 ligase parkin. Parkin and the protein kinase PINK1 collaborate to ubiquitylate mitochondrial membrane proteins of damaged mitochondria resulting in mitophagy (Lazarou et al., 2013). Dysregulation of mitophagy results in increased oxidative stress, which has been described as a characteristic of PD.
USP30 is the only reported mitochondrial deubiquitylating enzyme (DUB) and has been shown to have a role in maintenance of mitochondrial morphology (Nakamura and Hirose 2008). Recently it has been demonstrated that USP30 opposes parkin-mediated mitophagy and that reduction of USP30 activity can rescue parkin-mediated defects in mitophagy (Bingol et al., 2014). Thus inhibition of USP30 is a potential therapeutic strategy for treatment of PD. Using our proprietary DUB screening platform UbiSphere™ we have discovered novel, potent inhibitors of USP30. In a high-throughput biochemical assay, we have identified a number of chemical series with low nanomolar potencies. These inhibitors have been shown to inhibit USP30 catalytic activity in cellular activity probe assays that measure target engagement with IC50s in the 100 nM range. Here we will present the development and in vivo characterisation of these inhibitors as potential therapeutics for PD or other mitochondrial dysfunctions.
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