Deubiquitinating enzymes (DUBs) remove ubiquitin from their substrates and, together with ubiquitin ligases, play an important role in the regulation of protein expression. PR-619 is a broad-range UDB inhibitor that led to cell morphological changes, the upregulation of HSPs and accumulation of ubiquitinated protein species. PR-619 exhibits concentration dependent cytotoxicity in very narrow concentration range of 7 - 10 μM to OLN 93 cells. Treatment with 9 μM PR-619 causes an increase in the abundance of ubiquitinated protein, and proteasomal activity reduce to 50% within 24 h. PR-619 promotes the association of tau, ubiquitin and p62 with microtubules and alter their solubility[3]. In addition, Treatment with the PR-619 increased caspase-8 ubiquitination and caspase-8 enzymatic activity and sensitized normal fibroblasts to TRAIL-mediated apoptosis[4]. In vivo, administered daily with 100 μg PR-619 improves renal histopathological changes in mice with unilateral ureteral obstruction. Administration of PR-619 also attenuated renal fibrosis with downregulation of mesenchymal markers, extracellular matrix proteins, matrix metalloproteinases, apoptosis, macrophage infiltration, and the TGF-β1 mRNA level[5].
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