title: 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: Hybrigenics Pharma, 75014 Paris, France. fcolland@hybrigenics.com
authors: Frédéric
authors: F
authors: Colland
authors: Etienne
authors: E
authors: Formstecher
authors: Xavier
authors: X
authors: Jacq
authors: Céline
authors: C
authors: Reverdy
authors: Cécile
authors: C
authors: Planquette
authors: Susan
authors: S
authors: Conrath
authors: Virginie
authors: V
authors: Trouplin
authors: Julie
authors: J
authors: Bianchi
authors: Vasily N
authors: VN
authors: Aushev
authors: Jacques
authors: J
authors: Camonis
authors: Alessandra
authors: A
authors: Calabrese
authors: Catherine
authors: C
authors: Borg-Capra
authors: Wolfgang
authors: W
authors: Sippl
authors: Vincent
authors: V
authors: Collura
authors: Guillaume
authors: G
authors: Boissy
authors: Jean-Christophe
authors: JC
authors: Rain
authors: Philippe
authors: P
authors: Guedat
authors: Rémi
authors: R
authors: Delansorne
authors: Laurent
authors: L
authors: Daviet
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007192:Indenes / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000076084:Ubiquitin-Specific Peptidase 7
chemical_list: C546441:HBX 41,108; D007192:Indenes; D011480:Protease Inhibitors; D011719:Pyrazines; D016159:Tumor Suppressor Protein p53; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7