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Characterization of molecular and structural determinants of selective estrogen receptor downregulators

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Abstract

Antiestrogens used for breast cancer therapy can be categorized into two classes that differ in their effect on estrogen receptor (ER) alpha stability. The selective estrogen receptor modulators (SERMs) stabilize ER alpha and the selective estrogen receptor downregulators (SERDs) cause a decrease in cellular ER alpha levels. A clinically relevant antiestrogen, GW7604, appears to work through a SERD-like mechanism, despite sharing the same molecular scaffold as 4-hydroxytamoxifen, a SERM. In order to investigate potential structural features of GW7604 responsible for SERD activity, GW7604 and two analogs were synthesized using a new, improved synthetic route and tested for their effects on ER alpha function and cell proliferation. The two analogs, which have an acrylamide or a methyl vinyl ketone replacing the acrylic acid group of GW7604, display lower binding affinity for ER alpha than GW7604, but show similar antagonism of estradiol-induced activation of ER alpha-mediated transcription as GW7604 and inhibit estradiol-induced proliferation of the MCF-7 cell line with a similar potency as GW7604. Unlike GW7604, neither analog has a significant effect on cellular ER alpha levels, suggesting that the carboxylate is a key determinant in GW7604 action and, for the first time, showing that this group is responsible for inducing ER alpha degradation in breast cancer cells.

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Acknowledgements

RVW acknowledges the Purdue Cancer Center, the Indiana Elks Charities and the Army Breast Cancer Research Program (BC030507) for supporting this work. KPN gratefully acknowledges the following agencies for supporting this work: the Walther Cancer Institute, U.S. Army Medical Research Acquisition Activity, Award Numbers DAMD 17-02-1-0418 and DAMD17-02-1-0419; American Cancer Society Research and Alaska Run for Woman Grant TBE-104125

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Authors and Affiliations

  1. Department of Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA

    Meiyun Fan, Lei Chen & Kenneth P. Nephew

  2. Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue Cancer Center, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN, 47907, USA

    Emily L. Rickert, Syed A. Aftab & Ross V. Weatherman

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  1. Meiyun Fan
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  2. Emily L. Rickert
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  3. Lei Chen
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  4. Syed A. Aftab
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  5. Kenneth P. Nephew
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  6. Ross V. Weatherman
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Corresponding author

Correspondence to Ross V. Weatherman.

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Fan, M., Rickert, E.L., Chen, L. et al. Characterization of molecular and structural determinants of selective estrogen receptor downregulators. Breast Cancer Res Treat 103, 37–44 (2007). https://doi.org/10.1007/s10549-006-9353-2

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  • DOI: https://doi.org/10.1007/s10549-006-9353-2

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