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

Abstract

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 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 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.

Effects of Tormentic Acid and the Extracts from Callistemon citrinus on the Production of Extracellular Proteases by Staphylococcus aureus

“…e computer modelling has proposed that triterpenes have the suitable molecular size fit into the hydrophobic interface site of the relaxed monomer, which inhibits the protease dimerisation [22]. Additional to the hydrophobic interactions, hydrogenbonding is also suggested between protease and hydroxyl/ carboxyl groups in triterpene scaffold [23]. Since the main objective of this study was to screen the inhibitory effect of tormentic acid and extracts from C. citrinus on protease production, further studies on other inhibition mechanisms using both biological assays and computer modelling need to be carried out in future studies.…”

Antiurolithiatic effects of pentacyclic triterpenes: The distance traveled from therapeutic aspects

“…Some of the licensed pentacyclic triterpenes include oleanolic acid and glycyrrhizic acid as drugs for the treatment of liver disease, asiaticoside for wound healing, corosolic acid, and gymnemic acids for diabetes (Alqahtani et al, 2013;Furtado et al, 2017;Sheng & Sun, 2011). These compounds have been reported to possess a variety of biological activities, such as antitumor, anti-inflammatory, antiviral, and antioxidant (Jing et al, 2018). Pentacyclic triterpenes have proved to be promising remedial agents for the aversion and treatment of diabetes (Castellano, Guinda, Delgado, Rada, & Cayuela, 2013;Nazaruk & Borzym-Kluczyk, 2015;Putta et al, 2016).…”

Targeting ubiquitin specific protease 7 in cancer: A deubiquitinase with great prospects

“…Another series of natural pentacyclic triterpenes has been documented as potent USP7 inhibitor. In this group, the most potent inhibitor is ursolic acid with IC 50 of 7.0 ± 1.5 μM, which inhibits myeloma cell proliferation and reduces expression of MDM2, UHRF1, and DNMT1 . In order to establish molecular basis of USP7 inhibition, 2 compounds, FT671 and FT827, have been reported.…”

“…In this group, the most potent inhibitor is ursolic acid with IC 50 of 7.0 ± 1.5 μM, which inhibits myeloma cell proliferation and reduces expression of MDM2, UHRF1, and DNMT1. 121 In order to establish molecular basis of USP7 inhibition, 2 compounds, FT671 and FT827, have been reported. Both compounds can bind to dynamic pocket near the catalytic center of apo-USP7, and FT671 can regulate P53, P21, and MDM2.…”