PR-619

Background

PR-619 is a small-molecule inhibitor that displays broad specificity toward several deubiquitylating enzymes, including members of the ubiquitin specific protease (USP) and the ubiquitin C-terminal hydrolase (UCH) subfamilies (1). The ubiquitin proteasome system involves protein ubiquitination by ubiquitinating enzymes followed by proteasomal degradation; the process is reversed by cysteine proteases known as deubiquitinating enzymes that cleave ubiquitin from ubiquitin-conjugated proteins (2). PR-619 treatment of cells resulted in the accumulation of polyubiquitinated proteins and was not related to any deficiency in proteasome activity (1). Likewise, PR-619 treatment of an oligodendroglial cell line led to the buildup of protein aggregates near the microtubule network and increased expression of heat shock proteins associated with the cellular stress response (3). Protein deubiquitination is related to the development of cisplatin-resistant metastatic bladder urothelial carcinoma in patients; PR-619 treatment was shown to relieve chemoresistance in urothelial carcinoma cells and in a mouse xenograft model (4).