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PNAS 102 (7): 2543-2548

Copyright © 2005 by the National Academy of Sciences.


Identification of pathway-selective estrogen receptor ligands that inhibit NF-{kappa}B transcriptional activity

Christopher C. Chadwick * {dagger}, Susan Chippari *, Edward Matelan {ddagger}, Lisa Borges-Marcucci §, Amy M. Eckert *, James C. Keith, Jr. ¶, Leo M. Albert ¶, Yelena Leathurby ¶, Heather A. Harris *, Ramesh A. Bhat *, Mark Ashwell {ddagger} ||, Eugene Trybulski {ddagger}, Richard C. Winneker *, Steven J. Adelman §, Robert J. Steffan {ddagger}, and Douglas C. Harnish §, **

*Women's Health Research Institute and Departments of {ddagger}Chemical and Screening Sciences and §Cardiovascular and Metabolic Disease Research, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426; and Department of Cardiovascular and Metabolic Disease Research, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140

Edited by Jan-Åke Gustafsson, Karolinska Institute, Huddinge, Sweden

Accepted for publication January 5, 2005.

Received for publication August 9, 2004.

Abstract: Inflammation is now recognized as a key component in a number of diseases such as atherosclerosis, rheumatoid arthritis, and inflammatory bowel disease. The transcription factor NF-{kappa}B has been shown to be involved in both the early and late stages of the inflammatory-proliferative process. In this report, we describe the identification of the pathway-selective estrogen receptor (ER) ligand, WAY-169916, that inhibits NF-{kappa}B transcriptional activity but is devoid of conventional estrogenic activity. This pathway-selective ligand does not promote the classic actions of estrogens such as stimulation of uterine proliferation or ER-mediated gene expression, but is a potent antiinflammatory agent, as demonstrated in the HLA-B27 transgenic rat model of inflammatory bowel disease. Our results indicate the potential utility of pathway-selective ER ligands such as WAY-169916 in the treatment of chronic inflammatory diseases.

Key Words: inflammation • therapy

Author contributions: C.C.C., J.C.K., H.A.H., E.T., R.C.W., S.J.A., R.J.S., and D.C.H. designed research; C.C.C., S.C., E.M., L.B.-M., A.M.E., J.C.K., L.M.A., Y.L., H.A.H., M.A., R.J.S., and D.C.H. performed research; E.M., R.A.B., and R.J.S. contributed new reagents/analytic tools; C.C.C., S.C., E.M., L.B.-M., A.M.E., J.C.K., L.M.A., Y.L., H.A.H., R.J.S., and D.C.H. analyzed data; and D.C.H. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: ER, estrogen receptor; IBD, inflammatory bowel disease; E2, 17{beta}-estradiol; EE, 17{alpha}-ethynylestradiol; CK, creatine kinase; ICI, ICI 182,780; HAECT-1, human aorta endothelial cell 1.

{dagger} Present address: Life Diagnostics Inc., 909 Old Fern Hill Road, West Chester, PA 19380.

|| Present address: ArQule Research, 19 Presidential Way, Woburn, MA 01801.

** To whom correspondence should be addressed. E-mail: harnisd{at}

© 2005 by The National Academy of Sciences of the USA

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