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Colland, Frédéric; Formstecher, Etienne; Jacq, Xavier; Reverdy, Céline; Planquette, Cécile; Conrath, Susan; Trouplin, Virginie; Bianchi, Julie; Aushev, Vasily N; Camonis, Jacques; Calabrese, Alessandra; Borg-Capra, Catherine; Sippl, Wolfgang; Collura, Vincent; Boissy, Guillaume; Rain, Jean-Christophe; Guedat, Philippe; Delansorne, Rémi; Daviet, Laurent
Molecular cancer therapeutics, 08/2009, Letnik: 8, Številka: 8Journal Article
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.Mol Cancer Ther 2009;8(8):2286–95
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in: SICRIS
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