Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells.
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.
Colland
Frédéric
F
Hybrigenics Pharma, 75014 Paris, France. fcolland@hybrigenics.com
Formstecher
Etienne
E
Jacq
Xavier
X
Reverdy
Céline
C
Planquette
Cécile
C
Conrath
Susan
S
Trouplin
Virginie
V
Bianchi
Julie
J
Aushev
Vasily N
VN
Camonis
Jacques
J
Calabrese
Alessandra
A
Borg-Capra
Catherine
C
Sippl
Wolfgang
W
Collura
Vincent
V
Boissy
Guillaume
G
Rain
Jean-Christophe
JC
Guedat
Philippe
P
Delansorne
Rémi
R
Daviet
Laurent
L
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
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