Characterization of molecular and structural determinants of selective estrogen receptor downregulators

Meiyun Fan, Emily L. Rickert, Lei Chen, Syed A. Aftab, Kenneth P. Nephew, Ross V. Weatherman

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)37-44
Number of pages8
JournalBreast Cancer Research and Treatment
Volume103
Issue number1
DOIs
StatePublished - Jun 1 2007

Keywords

  • Antiestrogen
  • Estrogen receptor degradation
  • GW5638
  • GW7604
  • Selective estrogen receptor downregulator
  • Selective estrogen receptor modulator
  • Tamoxifen

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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