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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 ß

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

Requests for reprints: Michael B. Sporn, Department of Pharmacology, Dartmouth Medical School, Hanover, NH 03755. Phone: 603-650-6557; Fax: 603-650-1129. E-mail: Michael.Sporn{at}dartmouth.edu

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) ß 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 IKKß directly. [Mol Cancer Ther 2006;5(12):3232–9]

Grant support: NIH grant RO1 CA78814, National Foundation for Cancer Research (M.B. Sporn), Dartmouth College class of 1934, and Reata Pharmaceuticals, Inc. M.M. Yore is an Albert J. Ryan Fellow.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/31/06; revised 10/ 2/06; accepted 10/27/06.

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