Characterization of naturally occurring pentacyclic triterpenes as novel inhibitors of deubiquitinating protease USP7 with anticancer activity in vitro

Bo JING1, Meng LIU1, Li YANG1, Hai-yan CAI1, Jie-bo CHEN1, Ze-xi LI1, Xi KOU1, Yun-zhao WU1, Dong-jun QIN1, Li ZHOU2, Jin JIN1, Hu LEI1, Han-zhang XU1, Wei-wei WANG1, Ying-li WU1
1 Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2 Department of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
Correspondence to: Wei-wei WANG:, Ying-li WU:,
DOI: 10.1038/aps.2017.119
Received: 5 April 2017
Accepted: 21 July 2017
Advance online: 23 November 2017


Deubiquitinating protease USP7 is a promising therapeutic target for cancer treatment, and interest in developing USP7 inhibitors has greatly increased. In the present study, we reported a series of natural pentacyclic triterpenes with USP7 inhibitory activity in vitro. Among them, both the ursane triterpenes and oleanane triterpenes were more active than the lupine triterpenes, whereas ursolic acid was the most potent with IC50 of 7.0±1.5 μmol/L. Molecular docking studies showed that ursolic acid might occupy the ubiquitin binding pocket of USP7, with the 17-carboxyl group and 3-hydroxyl group playing a vital role in the USP7-ursolic acid interaction. Using the cellular thermal shift assay, we demonstrated that ursolic acid interacted with USP7 in RPMI8226 human myeloma cells. Ursolic acid dose-dependently inhibited the proliferation of the myeloma cells with IC50 of 6.56 μmol/L, accompanied by reductions in USP7 substrates such as MDM2, UHRF1 and DNMT1. Overexpression of USP7 partially, but significantly attenuated ursolic acid-induced cell death as well as downregulation of MDM2, UHRF1 and DNMT1. In conclusion, we demonstrate for the first time that pentacyclic triterpenes represent a novel scaffold for developing USP7 inhibitors and that USP7 inhibition contributes to the anti-cancer effect of ursolic acid.
Keywords: USP7; pentacyclic triterpenes; ursolic acid; anticancer agent; RPMI8226 human myeloma cells; UHRF1

Article Options

Download Citation

Cited times in Scopus