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
Open Access
- 1 December 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 5 (12), 3232-3239
- https://doi.org/10.1158/1535-7163.mct-06-0444
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 IκB kinase (IKK) β and that it thereby inhibits binding of nuclear factor-κB to DNA and subsequent transcriptional activation. Pretreatment of cells with CDDO-Im prevents IκBα phosphorylation and degradation in response to tumor necrosis factor α. 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 IKKβ directly. [Mol Cancer Ther 2006;5(12):3232–9]Keywords
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