P22077

P22077 is a dual inhibitor of the deubiquitylating enzymes ubiquitin-specific protease 7 (USP7) and USP47 (EC₅₀s = 8.01 and 8.74 µM, respectively, in a fluorescence-based enzyme assay).¹ It is selective for USP7 and USP47 over other USPs and proteases with EC₅₀ values greater than 50 µM. P22077 (25 µM) induces the accumulation of polyubiquitinated proteins in HEK293 cells. In neuroblastoma cells in vitro, P22077 blocks deubiquitylation of HDM2, a protein that normally deubiquitinates the tumor suppressor p53 leading to its degradation.² When used at concentrations of 10 and 20 µM, it amplifies the cytotoxicity and p53-mediated apoptosis of doxorubicin (Item No. 15007) and etoposide (Item No. 12092) in neuroblastoma cells. P22077 inhibits tumor growth in neuroblastoma mouse xenograft models when administered at a dose of 20 mg/kg per day.

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1. Altun, M., Kramer, H.B., Willems, L.I., et al. Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes. Chem. Biol. 18(11), 1401-1412 (2011).

2. Fan, Y.H., Cheng, J., Vasudevan, S.A., et al. USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis. Cell Death Dis. 4(10), e867 (2013).