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 IKB kinase (IKK) B and that it thereby inhibits binding of nuclear factor-KB to DNA and subsequent transcriptional activation. Pretreatment of cells with

more »

... m prevents IKBA phosphorylation and degradation in response to tumor necrosis factor A. 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 IKKB directly. [Mol Cancer Ther 2006;5(12):3232 -9]