RT Journal Article
SR Electronic
T1 Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 2286
OP 2295
DO 10.1158/1535-7163.MCT-09-0097
VO 8
IS 8
A1 Colland, Frédéric
A1 Formstecher, Etienne
A1 Jacq, Xavier
A1 Reverdy, Céline
A1 Planquette, Cécile
A1 Conrath, Susan
A1 Trouplin, Virginie
A1 Bianchi, Julie
A1 Aushev, Vasily N.
A1 Camonis, Jacques
A1 Calabrese, Alessandra
A1 Borg-Capra, Catherine
A1 Sippl, Wolfgang
A1 Collura, Vincent
A1 Boissy, Guillaume
A1 Rain, Jean-Christophe
A1 Guedat, Philippe
A1 Delansorne, Rémi
A1 Daviet, Laurent
YR 2009
UL http://mct.aacrjournals.org/content/8/8/2286.abstract
AB 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 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]