The intriguing role of USP30 inhibitors as deubiquitinating enzymes from the patent literature since 2013.

INTRODUCTION: Ubiquitin specific peptidase 30 (USP30) is a mitochondrial deubiquitinase that antagonizes ubiquitination-mediated mitophagy of damaged or impaired mitochondria driven by the activity of PARK2/Parkin ubiquitin ligase and PINK1 protein kinase. Researchers have related low levels of USP30 to enhanced mitophagy and therefore have been pursuing mitophagy activation utilizing USP30 inhibitors as an alternative approach to target neurodegenerative disorders and other human diseases associated with defective mitophagy. AREAS COVERED: This review covers the research and patent literature on the discovery and development of USP30 inhibitors since 2013. EXPERT OPINION: Strategies toward mitophagy activation utilizing small-molecule inhibitors of USP30 have emerged as alternative pathways for the potential treatment of many human diseases. Research efforts have led to identifying potent and selective small-molecule USP30 inhibitors. Most small-molecule USP30 inhibitors share a common N-cyano motif that binds covalently to the target. Non-covalently binding inhibitors have recently been disclosed as well. Lead compounds exhibit satisfactory inhibitory activities and are currently in preclinical development. Regrettably, complete pharmacological characterization and in vivo evaluation to validate and prove the therapeutic potential is lacking. Target validation could pave the way for discovering and developing USP30 inhibitors that could ultimately lead to marketed drugs.