This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ahmad, R. Articles by Kufe, D. PubMed PubMed Citation Articles by Ahmad, R. Articles by Kufe, D.

Triterpenoid CDDO-Methyl Ester Inhibits the Janus-Activated Kinase-1 (JAK1)Signal Transducer and Activator of Transcription-3 (STAT3) Pathway by Direct Inhibition of JAK1 and STAT3

¹ Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts and ² Reata Pharmaceuticals, Inc., Dallas, Texas

Requests for reprints: Donald Kufe, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: 617-632-3141; E-mail: donald_kufe{at}dfci.harvard.edu.

Key Words: triterpenoids • CDDO-Me • JAK1 • STAT3 • IL-6

The C-28 methyl ester of the oleane triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) induces apoptosis of human cancer cells by disrupting redox balance and is in clinical trials. CDDO-Me contains ,β-unsaturated carbonyl groups that form reversible adducts with thiol nucleophiles. The present studies show that CDDO-Me blocks interleukin-6 (IL-6)–induced and constitutive activation of the Janus-activated kinase 1 (JAK1) in cells. In support of a direct mechanism, CDDO-Me forms adducts with JAK1 at Cys¹⁰⁷⁷ in the kinase domain and inhibits JAK1 activity. In concert with these results, CDDO-Me blocked IL-6–induced and constitutive activation of signal transducer and activator of transcription 3 (STAT3). Moreover, we show that CDDO-Me (a) binds directly to STAT3 by a mechanism dependent on the alkylation of Cys²⁵⁹ and (b) inhibits the formation of STAT3 dimers. These findings indicate that CDDO-Me inhibits activation of the JAK1STAT3 pathway by forming adducts with both JAK1 and STAT3. [Cancer Res 2008;68(8):2920–6]