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

• Published in: Acta pharmacologica Sinica Vol. 39; no. 3; pp. 492 - 498
• Main Authors: Jing, Bo, Liu, Meng, Yang, Li, Cai, Hai-yan, Chen, Jie-bo, Li, Ze-xi, Kou, Xi, Wu, Yun-zhao, Qin, Dong-jun, Zhou, Li, Jin, Jin, Lei, Hu, Xu, Han-zhang, Wang, Wei-wei, Wu, Ying-li
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2018; Nature Publishing Group
• Subjects: Acids; Antineoplastic Agents - pharmacology; Antitumor activity; Biomedical and Life Sciences; Biomedicine; Cancer; CCAAT-Enhancer-Binding Proteins - metabolism; Cell death; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism; DNMT1 protein; Dose-Response Relationship, Drug; Humans; Hydroxyl groups; Immunology; Inhibitors; Internal Medicine; MDM2 protein; Medical Microbiology; Molecular Docking Simulation; Multiple myeloma; Myeloma; Neoplasms - drug therapy; Neoplasms - pathology; Original; original-article; Pentacyclic Triterpenes - pharmacology; Pharmacology/Toxicology; Protease; Protease inhibitors; Proteinase; Proteinase inhibitors; Proto-Oncogene Proteins c-mdm2 - metabolism; Structure-Activity Relationship; Therapeutic applications; Triterpenes; Triterpenes - antagonists & inhibitors; Triterpenes - pharmacology; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitin-Specific Peptidase 7 - antagonists & inhibitors; Ubiquitin-Specific Peptidase 7 - biosynthesis; Ursolic Acid; Vaccine; pentacyclic triterpenes; USP7; RPMI8226 human myeloma cells; UHRF1; anticancer agent; ursolic acid
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2017.119

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 IC 50 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 IC 50 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.