HBX 41108 is a potent inhibitor of USP7 with IC50 value of 424 nM [1].
Ubiquitin-specific-processing protease 7 (USP7) is a ubiquitin specific protease and removes ubiquitin from specific protein substrates. USP7 can deubiquitinate p53, protecting p53 from Mdm2-mediated degradation and involving the oncogenic stabilization of p53.
HBX 41108 is an uncompetitive and reversible USP7 inhibitor. HBX 41108 inhibited USP7-mediated p53 deubiquitination with IC50 value of 0.8 μM in a dose-dependent way and was only weakly active against the aspartic, serine and metalloproteases tested with IC50 > 10 μM. In HCT116 cells, HBX 41108 increased the levels of p53 and p21cip1/waf, which was the product of p53 target genes. In HEK293 cells, HBX 41108 increased the level of polyubiquitinated forms of p53 and reduced Mdm2 levels. In HCT116 colon cancer cells, HBX 41108 inhibited cell proliferation with IC50 value of 1 μM in a dose-dependent way and induced apoptosis in a dose-dependent manner [1]. In COS7 cells, HBX 41108 inhibited PPARγ stability induced by USP7 and decreased the basal transcriptional activity of PPARγ by 70% [2].
References:
[1]. Colland F, Formstecher E, Jacq X, et al. Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells. Mol Cancer Ther, 2009, 8(8): 2286-2295.
[2]. Lee KW, Cho JG, Kim CM, et al. Herpesvirus-associated Ubiquitin-specific Protease (HAUSP) Modulates Peroxisome Proliferator-activated Receptor γ (PPARγ) Stability through Its Deubiquitinating Activity. J Biol Chem, 2013, 288(46): 32886-32896.
