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

The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) 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-Im is a direct inhibitor of IkappaB kinase (IKK) beta and that it thereby inhibits binding of nuclear factor-kappaB to DNA and subsequent transcriptional activation. Pretreatment of cells with CDDO-Im prevents IkappaBalpha phosphorylation and degradation in response to tumor necrosis factor alpha. The kinetics of this inhibition by CDDO-Im are rapid and occur within 15 min. A biotinylated analogue of CDDO-Im showed that CDDO-Im binds to the IKK signalsome. Furthermore, we show that Cys(179) on IKK is a target for CDDO-Im. This is the first report to show that this novel synthetic triterpenoid binds to and inhibits IKKbeta directly.