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PR-619 is a broad-range DUB inhibitor with potential for further development as a chemotherapeutic agent in cancer therapy. IC50 Value: 3.93 uM (EC50, USP4), 7.2 uM (EC50, USP2 core), 5.10 uM (EC50, USP20) [1] Target: DUBs in vitro: PR-619 induces HCT116 cell death with EC50 values of 6.3 uM [1]. The general deubiquitylase (DUB) inhibitor, PR-619 attenuated KCa3.1 degradation, indicative of deubiquitylation being required for lysosomal delivery [2]. Proteasome inhibition by MG-132 and deubiquitinase inhibition by PR-619 induces significant changes to the ubiquitin landscape, but that not all ubiquitination sites regulated by MG-132 and PR-619 are likely substrates for the ubiquitin-proteasome system [3]. Cells were incubated with PR-619, a broad-range, reversible inhibitor of ubiquitin isopeptidases. Incubation with PR-619 led to morphological changes, the upregulation of heat shock proteins (HSP), including HSP70 and alphaB-crystallin, and to protein aggregates near the MTOC, containing ubiquitin, HSPs, and the ubiquitin binding protein p62, which may provide a link between the UPS and autophagy. Thus, inhibition of DUB activity caused stress responses and the formation of protein aggregates resembling pathological inclusions observed in aggregopathies [4]. in vivo:
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