Deubiquitylases, a new class of drug targets for cancer and neurodegeneration

I will provide an overview of the family of deubiquitylase enzymes and describe the logic behind investigating them as drug targets.

 

Working as part of a large consortium we have developed highly specific USP7 inhibitors which reduce MDM2 levels, increase p53 and inhibit tumour growth. High resolution structural studies reveal how such specificity is achieved. I will also discuss the role of Parkinsons Disease associated proteins PINK1 and Parkin in mitophagy. We propose that  the deubiquitylase USP30 limits Parkin activity and may therefore represent an actionable target. We also show that basal mitophagy is largely PINK1/Parkin independent, but that loss of USP30 reveals a PINK1-dependent component.

 

Finally we show that a fraction of USP30 localises to peroxisomes and regulates their turnover through pexophagy.