The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-κB activation through direct inhibition of IκB kinase β

Abstract

The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1, 9(11)-dien-28-oyl]imidazole (CDDO-lm) is a multifunctional agent with potent anti-inflammatory, antiproliferative, cytoprotective, and apoptotic activities, whose molecular targets are unknown. Using both cell-free and cellular assays, we show that CDDO-lm is a direct inhibitor of lκB kinase (IKK) β and that it thereby inhibits binding of nuclear factor-κB to DNA and subsequent transcriptional activation. Pretreatment of cells with CDDO-lm prevents IκBα phosphorylation and degradation in response to tumor necrosis factor α. The kinetics of this inhibition by CDDO-lm are rapid and occur within 15 min. A biotinylated analogue of CDDO-lm showed that CDDO-lm binds to the IKK signalsome. Furthermore, we show that CYS179 on IKK is a target for CDDO-lm. This is the first report to show that this novel synthetic triterpenoid binds to and inhibits IKKβ directly. Copyright © 2006 American Association for Cancer Research.