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
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
收藏
页码:2286 / 2295
页数:10
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