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

被引：270

作者：

Colland, Frederic ^{[1
]}

Formstecher, Etienne ^{[1
]}

Jacq, Xavier ^{[1
]}

Reverdy, Celine ^{[1
]}

Planquette, Cecile ^{[1
]}

Conrath, Susan ^{[1
]}

Trouplin, Virginie ^{[1
]}

Bianchi, Julie ^{[1
]}

Aushev, Vasily N. ^{[2
]}

Camonis, Jacques ^{[2
]}

Calabrese, Alessandra ^{[1
]}

Borg-Capra, Catherine ^{[1
]}

Sippl, Wolfgang ^{[3
]}

Collura, Vincent ^{[1
]}

Boissy, Guillaume ^{[1
]}

Rain, Jean-Christophe ^{[1
]}

Guedat, Philippe ^{[1
]}

Delansorne, Remi ^{[1
]}

Daviet, Laurent ^{[1
]}

机构：

[1] Hybrigen Pharma, F-75014 Paris, France

[2] INSERM, Inst Curie, Paris, France

[3] Univ Halle Wittenberg, Dept Pharmaceut Chem, Halle, Germany

来源：

MOLECULAR CANCER THERAPEUTICS | 2009年 / 8卷 / 08期

关键词：

DEUBIQUITINATING ENZYMES; P53-MDM2; PATHWAY; IN-VIVO; HAUSP; CANCER; MDM2; DESTABILIZATION; ANTAGONISTS; DISCOVERY; AGENTS;

D O I：

10.1158/1535-7163.MCT-09-0097

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 IC50 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 p 53, 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. [Mol Cancer Ther 2009;8(8):2286-95]

引用

页码：2286 / 2295

页数：10

共 35 条

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