P22077 is an inhibitor of ubiquitin specific protease USP7 (EC50 = 8.6 μM). P22077 also inhibits the deubiquitinase USP47.
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Deubiquitinating enzymes (DUBs) function to remove covalently attached ubiquitin from proteins, thereby controlling substrate activity and/or abundance. More than the half of DUBs belong to the ubiquitin-specific protease (USP) subfamily. USP7 is the most widely studied DUB and is well known as herpes-associated USP (HAUSP). USP7 can influence the location, activation , and stability of its substrates[3]. P22077 is an inhibitor of USP7 with IC50 value of 6 and 10 μM for USP10 and USP7, respectively[4]. In vitro, P22077 activates p53 and its targeted gene p21 (cyclin-dependent kinase inhibitor 1) in human colon carcinoma HCT116 cells. P22077 greatly reduced the cell viability and induced apoptosis of IMR-32, NGP, CHLA-255, and SH-SY5Y cells but not that of NB-19 and SK-N-AS cells at concentration ranging in 1 - 20 μM. P22077 stabilized p53 by inducing HDM2 protein degradation, and augmented the cytotoxic effects of doxorubicin and etoposide in neuroblastoma cells. In vivo, administration P2207 at dose of 15 mg/kg daily for 3 weeks significantly inhibited tumor growth in the orthotopic neuroblastoma mouse model[5]. Treatment with P2207 on the dose of 20 mg/kg daily for 30 days significantly suppressed the growth of MYCN-amplified human neuroblastoma cell lines in xenograft mouse models[6].
作用机制
P22077 covalently modify the catalytic cysteine of USP7 and induce a conformational switch in the enzyme associated with active site rearrangement[7].
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