Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells.

Détails

ID Serval
serval:BIB_CE23562CB9B1
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells.
Périodique
Molecular Cancer Therapeutics
Auteur(s)
Colland F., Formstecher E., Jacq X., Reverdy C., Planquette C., Conrath S., Trouplin V., Bianchi J., Aushev V.N., Camonis J., Calabrese A., Borg-Capra C., Sippl W., Collura V., Boissy G., Rain J.C., Guedat P., Delansorne R., Daviet L.
ISSN
1538-8514[electronic], 1535-7163[linking]
Statut éditorial
Publié
Date de publication
2009
Volume
8
Numéro
8
Pages
2286-2295
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.
Mots-clé
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
Oui
Création de la notice
16/06/2010 11:21
Dernière modification de la notice
20/08/2019 15:48
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