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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
Signal Transducer and Activator of Transcription-3 (STAT3) Pathway by Direct Inhibition of JAK1 and STAT31 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 JAK1
STAT3 pathway by forming adducts with both JAK1 and STAT3. [Cancer Res 2008;68(8):2920–6]
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