Abstract
Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaline Phosphatase / analysis
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Animals
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Antineoplastic Agents / analysis
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Benzopyrans / chemical synthesis
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Benzopyrans / chemistry
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Benzopyrans / pharmacology*
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Benzopyrans / therapeutic use
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Cell Proliferation / drug effects
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Estrogen Antagonists / analysis
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Estrogen Antagonists / chemical synthesis
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Estrogen Antagonists / pharmacology*
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Estrogen Antagonists / therapeutic use
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Estrogen Receptor alpha / drug effects
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Female
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Humans
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MCF-7 Cells
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Mammary Neoplasms, Experimental / drug therapy*
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Mice, Inbred BALB C
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Mice, Nude
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Protein Conformation, alpha-Helical / drug effects
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacology*
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Pyrrolidines / therapeutic use
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Selective Estrogen Receptor Modulators / analysis
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Selective Estrogen Receptor Modulators / chemical synthesis
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Selective Estrogen Receptor Modulators / pharmacology
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Stereoisomerism
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Uterus / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Benzopyrans
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Estrogen Antagonists
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Estrogen Receptor alpha
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OP-1074
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Pyrrolidines
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Selective Estrogen Receptor Modulators
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Alkaline Phosphatase