Related Experiment Videos
Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with
Niamh M O'Boyle1,2, Irene Barrett1, Lisa M Greene2
1School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin , 152-160 Pearse Street, Dublin 2 D02 R590, Ireland.
Journal of Medicinal Chemistry
|April 21, 2017
Summary
New benzoxepin-based compounds show promise as estrogen receptor (ER) targeted therapies. One compound selectively targets ERα for potential breast cancer treatment, while another probes ERβ
Area of Science:
- Medicinal Chemistry
- Endocrinology
- Molecular Biology
Background:
- Estrogen receptor alpha (ERα) is a key target for breast cancer therapeutics like tamoxifen and fulvestrant.
- Developing novel ER ligands with improved selectivity and efficacy is crucial for targeted cancer therapy.
Purpose of the Study:
- To synthesize and evaluate novel benzoxepin-based compounds as ligands for estrogen receptors.
- To assess the ERα and ERβ selectivity and antiproliferative effects of these novel compounds.
- To explore the potential of these compounds as therapeutic agents or research probes.
Main Methods:
- Synthesis of three series of benzoxepin-based ER ligands with varying substituents (acrylic acid, acrylamide, saturated carboxylic acid).
- In vitro evaluation of ligand binding affinity (IC50 values) and ERα/ERβ selectivity.
- Assessment of antiproliferative activity in MCF-7 breast cancer cells.
- Molecular docking studies to understand ligand-receptor interactions.
Main Results:
- All synthesized benzoxepin derivatives exhibited high affinity for ER, with nanomolar binding values.
- Series I compounds, particularly compound 13e (phenylpenta-2,4-dienoic acid), demonstrated ERα selectivity, antiproliferative effects, and downregulated ERα/ERβ expression.
- Compound 22 (phenoxybutyric acid derivative) selectively downregulated ERβ without antiproliferative activity.
Conclusions:
- Compound 13e is a promising lead for developing a clinically relevant selective estrogen receptor degrader (SERD).
- Compound 22 serves as a valuable experimental tool for investigating the role of ERβ in cancer.
- Benzoxepin scaffold offers a versatile platform for designing selective ER modulators.