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Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
Published on: December 19, 2018
Design, synthesis, and in-silico study of novel triarylethylene analogs with dual anti-estrogenic and serotonergic
Tammy Mostafa1, Miriam Albeir1, Jannette Wober2
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
Abstract:
Estrogen receptor is an important target in breast cancer. Serotonin receptors (5-HT2A and 5-HT2C , in particular) were investigated for a potential role in development and progression of breast cancer. Ligands that interact with estrogenic receptors influence the emotional state of females. Thus, designing selective estrogen receptor modulator (SERM) analogs with potential serotonergic activity is a plausible approach. The dual ligands can augment cytotoxic effect of SERMs, help in both physical and emotional menopausal symptom relief, enhance cognitive function and support bone health. Herein, we report triarylethylene analogs as potential candidates for treatment of breast cancer. Compound 2e showed (ERα relative β- galactosidase activity = 0.70), 5-HT2A (Ki = 0.97 µM), and 5-HT2C (Ki = 3.86 µM). It was more potent on both MCF-7 (GI50 = 0.27 µM) and on MDA-MB-231 (GI50 = 1.86 µM) compared to tamoxifen (TAM). Compound 4e showed 40 times higher antiproliferative activity on MCF-7 and 15 times on MDA-MBA compared to TAM. Compound 4e had higher average potency than TAM on all nine tested cell line panels. Our in-silico model revealed the binding interactions of compounds 2 and 2e in the three receptors; further structural modifications are suggested to optimize binding to the ERα, 5-HT2A , and 5-HT2C .
Insights
New triarylethylene analogs show promise as dual-acting drugs for breast cancer treatment. These compounds target both estrogen receptors and serotonin receptors, offering potential for improved efficacy and symptom management.
Area of Science:
- Oncology
- Pharmacology
- Neuroscience
Background:
- Estrogen receptors are key targets in breast cancer therapy.
- Serotonin receptors (5-HT2A and 5-HT2C) may play a role in breast cancer development.
- Selective estrogen receptor modulators (SERMs) can impact emotional state, suggesting a link between estrogen and serotonin pathways.
Purpose of the Study:
- To design and investigate novel selective estrogen receptor modulator (SERM) analogs with dual serotonergic activity for breast cancer treatment.
- To develop potential therapeutic agents that can augment cytotoxic effects, alleviate menopausal symptoms, enhance cognition, and support bone health.
- To explore triarylethylene analogs as candidates for combined estrogenic and serotonergic modulation.
Main Methods:
- Synthesis and evaluation of triarylethylene analogs.
- Assessment of binding affinities for estrogen receptors (ERα) and serotonin receptors (5-HT2A, 5-HT2C).
- In vitro antiproliferative assays using breast cancer cell lines (MCF-7, MDA-MB-231) and comparison with tamoxifen (TAM).
- In-silico modeling to analyze binding interactions within the target receptors.
Main Results:
- Compound 2e demonstrated activity at ERα, 5-HT2A (Ki = 0.97 µM), and 5-HT2C (Ki = 3.86 µM), showing greater potency than tamoxifen against MCF-7 and MDA-MB-231 cell lines.
- Compound 4e exhibited significantly higher antiproliferative activity compared to tamoxifen, with 40 times greater potency on MCF-7 and 15 times on MDA-MB-231.
- Compound 4e demonstrated superior average potency across nine tested cell line panels compared to tamoxifen.
- In-silico analysis provided insights into the binding interactions of compounds 2 and 2e with ERα, 5-HT2A, and 5-HT2C receptors.
Conclusions:
- Triarylethylene analogs represent promising candidates for novel breast cancer therapeutics with dual estrogenic and serotonergic activity.
- Compounds 2e and 4e show enhanced potency and antiproliferative effects compared to tamoxifen, suggesting potential for improved treatment outcomes.
- Further structural optimization based on in-silico models is recommended to enhance binding affinity and therapeutic efficacy.
- These dual-acting ligands offer a potential strategy for managing both the physical and emotional aspects of breast cancer and its treatment.
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