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J. Biol. Chem., Vol. 281, Issue 47, 35764-35769, November 24, 2006

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Triterpenoid CDDO-Me Blocks the NF-B Pathway by Direct Inhibition of IKK on Cys-179^*

Rehan Ahmad, Deepak Raina, Colin Meyer, Surender Kharbanda, and Donald Kufe¹

From the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 and Reata Pharmaceuticals, Inc., Dallas, Texas 75207

The novel oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid (CDDO) and the C-28 methyl ester (CDDO-Me) induce apoptosis of human tumor cells by disruption of redox balance and are currently in clinical trials. The present studies show that CDDO and CDDO-Me block tumor necrosis factor-induced targeting of NF-B p65 to the nucleus. CDDO-Me also blocked tumor necrosis factor -induced phosphorylation of IB. In concert with these results, we found that CDDO-Me inhibits IB kinase (IKK) activity in cells. In support of a direct mechanism, CDDO-Me inhibited recombinant IKK activity in vitro. The results also demonstrate that (i) CDDO and CDDO-Me form adducts with IKK, but not IKK with mutation of Cys-179 to Ala, and (ii) CDDO-Me inhibits IKK by a mechanism dependent on oxidation of Cys-179. These findings indicate that CDDO and CDDO-Me directly block IKK activity and thereby the NF-B pathway by interacting with Cys-179 in the IKK activation loop.

Received for publication, July 27, 2006 , and in revised form, September 14, 2006.

^* This work was supported by NCI, National Institutes of Health Grants CA42802, CA100707, and CA98628. 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.

¹ To whom correspondence should be addressed. Tel.: 617-632-3141; Fax: 617-632-2934; E-mail: donald_kufe{at}dfci.harvard.edu.

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