Cytotoxic unsaturated electrophilic compounds commonly target the ubiquitin proteasome system

Abstract

A large number of natural products have been advocated as anticancer agents. Many of these compounds contain functional groups characterized by chemical reactivity. It is not clear whether distinct mechanisms of action can be attributed to such compounds. We used a chemical library screening approach to demonstrate that a substantial fraction (~20%) of cytotoxic synthetic compounds containing Michael acceptor groups inhibit proteasome substrate processing and induce a cellular response characteristic of proteasome inhibition. Biochemical and structural analyses showed binding to and inhibition of proteasome-associated cysteine deubiquitinases, in particular ubiquitin specific peptidase 14 (USP14). The results suggested that compounds bind to a crevice close to the USP14 active site with modest affinity, followed by covalent binding. A subset of compounds was identified where cell death induction was closely associated with proteasome inhibition and that showed significant antineoplastic activity in a zebrafish embryo model. These findings suggest that proteasome inhibition is a relatively common mode of action by cytotoxic compounds containing Michael acceptor groups and help to explain previous reports on the antineoplastic effects of natural products containing such functional groups.

A Novel Approach to Substituted α-Carbamoyl Phosphonates: Useful Reagents for the Horner–Wadsworth–Emmons Olefination

“…2 It is also notable that in the natural product domain, unrivaled by its success as a source of drug leads, Michael acceptor motifs are frequently encountered 3 and could be responsible for the antineoplastic activity displayed by such naturally occurring compounds. 4 The selective cytotoxic activity displayed by Michael acceptors towards cancer cells could be attributable to their interaction with the components of critical cell survival mechanisms (such as ubiquitin proteasome system 5 or thioredoxin system 6 ).…”

Antiproliferative, cholinesterase and phosphodiesterase inhibitory activity of the DCM sub-extract of Uvaria alba: In vitro and in silico perspectives

“…Molecular docking and molecular dynamics simulations are popular computational methodologies adopted for drug discovery [8]. Among the recently discovered drug targets using computational techniques is the ubiquitin-proteasome pathway, which is involved in the synchronized proteolysis of cyclins and cyclin-dependent kinase inhibitors critical for cell cycle progression [9,10]. Protein ubiquitination is primarily regulated by deubiquitinases (DUBs).…”

“…Thus, inhibiting DUBs, such as ubiquitin specific peptidase 14 (USP14), may induce apoptosis in a variety of cancer cells while conferring low cytotoxicity to normal cells [10]. Another cytoprotective mechanism of the body against oxidative stress involves the KEAP1-Nrf2-ARE pathway [11].…”

“…Recent studies showed that disrupting the KEAP1-Nrf2-ARE pathway and consequently enhancing Nrf2 activity is a promising strategy for preventing chronic diseases involving oxidative stress and inflammation [12]. Natural products, particularly those with unsaturated electrophilic moieties, have been identified to target USP14 and KEAP1 [10,13].…”

(E)-3-Arylidene-4-diazopyrrolidine-2,5-diones: Preparation and Use in RhII-Catalyzed X–H Insertion Reactions towards Novel, Medicinally Important Michael Acceptors

“…4 Michael acceptors are often selective toward cancer cells and do not perturb vital processes of normal cells. This could be due to their intrusion in the critical survival mechanisms of cancer cells (such as overactive ubiquitin proteasome 5 or upregulated thioredoxin system 6 ).…”