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 mo

SUBMITTER: Selvaraju K 

PROVIDER: S-EPMC6614553 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature