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

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.

• Authors: Frédéric Colland, Etienne Formstecher, Xavier Jacq, Céline Reverdy, Cécile Planquette, Susan Conrath, Virginie Trouplin, Julie Bianchi, Vasily N Aushev, Jacques Camonis, Alessandra Calabrese, Catherine Borg-Capra, Wolfgang Sippl, Vincent Collura, Guillaume Boissy, Jean-Christophe Rain, Philippe Guedat, Rémi Delansorne, Laurent Daviet
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 8 Pg. 2286-95 (Aug 2009) ISSN: 1538-8514 [Electronic] United States
• PMID: 19671755 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HBX 41,108
• Indenes
• Protease Inhibitors
• Pyrazines
• Tumor Suppressor Protein p53
• USP7 protein, human
• Ubiquitin Thiolesterase
• Ubiquitin-Specific Peptidase 7

Topics

• 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, metabolism)
• Ubiquitin Thiolesterase (antagonists & inhibitors, metabolism)
• Ubiquitin-Specific Peptidase 7