Abstract
Orally bioavailable SERDs may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for patients with ER-positive endocrine-resistant breast cancer. We report the design and synthesis of a boronic acid modified fulvestrant (5, ZB716), which binds to ERα competitively (IC50 = 4.1 nM) and effectively downregulates ERα in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. Furthermore, It has superior oral bioavailability (AUC = 2547.1 ng·h/mL) in mice, indicating its promising clinical utility as an oral SERD.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Extramural
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Boronic Acids / chemical synthesis
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Boronic Acids / chemistry*
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Boronic Acids / pharmacology
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Breast Neoplasms
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Down-Regulation
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Drug Resistance, Neoplasm
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Estrogen Receptor alpha / metabolism
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Female
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Mice, Inbred C57BL
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Selective Estrogen Receptor Modulators / chemical synthesis
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Selective Estrogen Receptor Modulators / chemistry*
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Selective Estrogen Receptor Modulators / pharmacology
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Signal Transduction
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Stereoisomerism
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Sterols / chemical synthesis
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Sterols / chemistry*
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Sterols / pharmacology
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Tamoxifen / pharmacology
Substances
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Boronic Acids
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Estrogen Receptor alpha
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Selective Estrogen Receptor Modulators
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Sterols
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ZB716 compound
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Tamoxifen