DUB Inhibitor, PR-619

• CAT Number: I002906
• CAS Number: 2645-32-1
• Molecular Formula: C₇H₅N₅S₂
• Molecular Weight: 223.28
• Purity: ≥95%
• Target: DUB
• Solubility: DMSO: ≥ 21 mg/mL
• Storage: Store at -20°C
• IC50: 3.93 μM (EC50, USP4); 7.2 μM (EC50, USP2 core); 5.10 μM (EC50, USP20) [1]
• InChI: InChI=1S/C7H5N5S2/c8-2-13-4-1-5(14-3-9)7(11)12-6(4)10/h1H,(H4,10,11,12)
• InChIKey: ZXOBLNBVNROVLC-UHFFFAOYSA-N
• SMILES: N#CSC1=C(N)N=C(N)C(SC#N)=C1

PR-619 is a broad-range DUB inhibitor with potential for further development as a chemotherapeutic agent in cancer therapy.IC50 Value: 3.93 μM (EC50, USP4); 7.2 μM (EC50, USP2 core); 5.10 μM (EC50, USP20) [1]Target: DUBsin vitro: PR-619 induces HCT116 cell death with EC50 values of 6.3 μM [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 αB-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:

Reference

1:The Deubiquitinase Inhibitor PR-619 Sensitizes Normal Human Fibroblasts to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-mediated Cell Death. Crowder RN, Dicker DT, El-Deiry WS.J Biol Chem. 2016 Mar 11;291(11):5960-70. doi: 10.1074/jbc.M115.713545. Epub 2016 Jan 12. PMID: 26757822 Free PMC Article2:Inhibition of protein deubiquitination by PR-619 activates the autophagic pathway in OLN-t40 oligodendroglial cells. Seiberlich V, Borchert J, Zhukareva V, Richter-Landsberg C.Cell Biochem Biophys. 2013 Sep;67(1):149-60. doi: 10.1007/s12013-013-9622-8. PMID: 23686611 3:The small molecule inhibitor PR-619 of deubiquitinating enzymes affects the microtubule network and causes protein aggregate formation in neural cells: implications for neurodegenerative diseases. Seiberlich V, Goldbaum O, Zhukareva V, Richter-Landsberg C.Biochim Biophys Acta. 2012 Nov;1823(11):2057-68. doi: 10.1016/j.bbamcr.2012.04.011. Epub 2012 Apr 28. PMID: 22565157 Free Article