Research Articles: Therapeutics, Targets, and Development

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

^{1 1}Department of Pharmacology, Dartmouth Medical School and ²Department of Chemistry, Dartmouth College, Hanover, New Hampshire

	Abstract

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 IB kinase (IKK) and that it thereby inhibits binding of nuclear factor-B to DNA and subsequent transcriptional activation. Pretreatment of cells with CDDO-Im prevents IB phosphorylation and degradation in response to tumor necrosis factor . 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 Cys¹⁷⁹ on IKK is a target for CDDO-Im. This is the first report to show that this novel synthetic triterpenoid binds to and inhibits IKK directly. [Mol Cancer Ther 2006;5(12):3232-9]

Key Words: Triterpenoid, CDDO-Im, NF-B, IKK, Redox

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