This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wittmann, B. M. Articles by McDonnell, D. P. Search for Related Content PubMed PubMed Citation Articles by Wittmann, B. M. Articles by McDonnell, D. P.

Definition of Functionally Important Mechanistic Differences among Selective Estrogen Receptor Down-regulators

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina

Requests for reprints: Donald P. McDonnell, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813, Durham, NC 27710. Phone: 919-684-6035; Fax: 919-681-7139; E-mail: donald.mcdonnell{at}duke.edu.

One subclass of antiestrogens, the selective estrogen receptor down-regulators (SERDs), have received considerable attention of late as they competitively inhibit estrogen binding and induce a rapid, proteasome-dependent degradation of the receptor. Contained within this class of molecules is the steroidal antiestrogen ICI182,780 (faslodex), recently approved for the treatment of metastatic cancer, and GW5638/DPC974, a SERD that is currently being evaluated in the clinic. Given that mechanistic differences between different selective estrogen receptor modulators have been translated into important clinical profiles, it was of interest to determine if the SERD subclass of ligands were likewise functionally or mechanistically distinguishable. In this study, we show that although the steroidal and nonsteroidal SERDs target ER for degradation, the underlying mechanism(s) are different. Of note was the identification of a specific protein-protein interaction surface presented on ER in the presence of the ICI182,780-activated receptor which is required for degradation. Interestingly, this surface is also presented on ER in the presence of RU58,668, a SERD that is chemically distinct from ICI182,780. This surface is not required for GW5638-mediated degradation, and thus, this SERD seems to affect ER down-regulation by a different mechanism. These data suggest that sequencing of therapies using drugs of this class is likely to be possible. Finally, because of the unmet need for orally active SERDS that function similarly to ICI182,780, we have used the insights from these mechanistic studies to develop and validate a high-throughput screen for compounds of this class with improved pharmaceutical properties. [Cancer Res 2007;67(19):9549–60]

This article has been cited by other articles:

				A. M Davis, J. Mao, B. Naz, J. A Kohl, and C. S Rosenfeld Comparative effects of estradiol, methyl-piperidino-pyrazole, raloxifene, and ICI 182 780 on gene expression in the murine uterus J. Mol. Endocrinol., October 1, 2008; 41(4): 205 - 217. [Abstract] [Full Text] [PDF]