期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 16, 期 23, 页码 10075-10084出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.10.007
关键词
Estrogen receptor; Coactivator binding; Tamoxifen resistance; Protein-protein Interaction
资金
- National Institutes of Health [PHS 5R37 DK15556, F30 ES016484-01, NRSA 5 T32 GM070421]
- David Robertson Fellowship
Most patients with hormone-responsive breast cancer eventually develop resistance to traditional antiestrogens such as tamoxifen, and this has become a major obstacle in their treatment. We prepared and characterized the activity of a series of 16 guanylhydrazone small molecules that are designed to block estrogen receptor (ER) activity through a non-traditional mechanism, by directly interfering with coactivator binding to agonist-liganded ER. The inhibitory activity of these compounds was determined in cell-based transcription assays using ER-responsive reporter gene and mammalian two-hybrid assays. Several of the compounds gave IC50 values in the low micromolar range. Two secondary assays were used to confirm that these compounds were acting through the proposed non-traditional mode of estrogen inhibitory action and not as conventional antagonists at the ligand binding site. (c) 2008 Elsevier Ltd. All rights reserved.
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