CDDO-Me reveals USP7 as a novel target in ovarian cancer cells

Abstract

Deubiquitinating enzyme USP7 has been involved in the pathogenesis and progression of several cancers. Targeting USP7 is becoming an attractive strategy for cancer therapy. In this study, we identified synthetic triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid (CDDO-Me) as a novel inhibitor of USP7 but not of other cysteine proteases such as cathepsin B and cathepsin D. CDDO-Me inhibits USP7 activity via a mechanism that is independent of the presence of α, β-unsaturated ketones. Molecular docking studies showed that CDDO-Me fits well in the ubiquitin carboxyl terminus-binding pocket on USP7. Given that CDDO-Me is known to be effective against ovarian cancer cells, we speculated that CDDO-Me may target USP7 in ovarian cancer cells. We demonstrated that ovarian cancer cells have higher USP7 expression than their normal counterparts. Knockdown of USP7 inhibits the proliferation of ovarian cancer cells both in vitro and in vivo. Using the cellular thermal shift assay and the drug affinity responsive target stability assay, we further demonstrated that CDDO-Me directly binds to USP7 in cells, which leads to the decrease of its substrates such as MDM2, MDMX and UHRF1. CDDO-Me suppresses ovarian cancer tumor growth in an xenograft model. In conclusion, we demonstrate that USP7 is a novel target of ovarian cancer cells; targeting USP7 may contribute to the anti-cancer effect of CDDO-Me. The development of novel USP7 selective compounds based on the CDDO-Me-scaffold warrants further investigation.

Targeting the overexpressed USP7 inhibits esophageal squamous cell carcinoma cell growth by inducing NOXA‐mediated apoptosis

“…Recent reports showed that deubiquitinase USP7 play an important role in various pathways and involved in a variety of pathophysiological processes, including cancer . USP7 was expressed abnormally and correlated with tumor's prognosis in a tumor‐specific manner . However, little is known about the expression and role of USP7 in ESCC.…”

The USP7 Inhibitor P5091 Induces Cell Death in Ovarian Cancers with Different P53 Status

“…Recent investigations have linked the expression of deubiquitylase USP7 with poor prognosis in ovarian cancer [16, 35]. Therefore, in the current study we investigated the effectiveness of the USP7 inhibitor P5091 to suppress ovarian cancer growth in vitro .…”

CETSA quantitatively verifies in vivo target engagement of novel RIPK1 inhibitors in various biospecimens

“…This study demonstrates that CETSA is feasible to conduct comprehensive animal studies that enable to interpret the TE of a reversible kinase inhibitor in in vivo animal experiments, although a few groups have used this technology for tissue lysates 12 and animal experiments treated with irreversible compounds 5 and Michael acceptor inhibitor 10 . For clinical application, peripheral blood is easily accessible and widely used in research and toxicology.…”

“…demonstrated in vivo TE with TNP-470 which is a covalent inhibitor against methionine aminopeptidase-2 6 . Another group demonstrated qualitative TE in a xenograft model using Michael acceptor inhibitor 10 . However, covalent drugs are rarely considered in target-directed drug discovery owing to safety concerns 11 .…”