Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells.
Details
Serval ID
serval:BIB_CE23562CB9B1
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells.
Journal
Molecular Cancer Therapeutics
ISSN
1538-8514[electronic], 1535-7163[linking]
Publication state
Published
Issued date
2009
Volume
8
Number
8
Pages
2286-2295
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Deregulation of the ubiquitin/proteasome system has been implicated in the pathogenesis of many human diseases, including cancer. Ubiquitin-specific proteases (USP) are cysteine proteases involved in the deubiquitination of protein substrates. Functional connections between USP7 and essential viral proteins and oncogenic pathways, such as the p53/Mdm2 and phosphatidylinositol 3-kinase/protein kinase B networks, strongly suggest that the targeting of USP7 with small-molecule inhibitors may be useful for the treatment of cancers and viral diseases. Using high-throughput screening, we have discovered HBX 41,108, a small-molecule compound that inhibits USP7 deubiquitinating activity with an IC(50) in the submicromolar range. Kinetics data indicate an uncompetitive reversible inhibition mechanism. HBX 41,108 was shown to affect USP7-mediated p53 deubiquitination in vitro and in cells. As RNA interference-mediated USP7 silencing in cancer cells, HBX 41,108 treatment stabilized p53, activated the transcription of a p53 target gene without inducing genotoxic stress, and inhibited cancer cell growth. Finally, HBX 41,108 induced p53-dependent apoptosis as shown in p53 wild-type and null isogenic cancer cell lines. We thus report the identification of the first lead-like inhibitor against USP7, providing a structural basis for the development of new anticancer drugs.
Keywords
Apoptosis, Cell Line, Tumor, Cell Proliferation, Cells, Cultured, Dose-Response Relationship, Drug, Humans, Indenes/pharmacology, Protease Inhibitors/pharmacology, Pyrazines/pharmacology, Tumor Suppressor Protein p53/genetics, Tumor Suppressor Protein p53/metabolism, Ubiquitin Thiolesterase/antagonists & inhibitors, Ubiquitin Thiolesterase/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
16/06/2010 12:21
Last modification date
20/08/2019 16:48