Related Experiment Video
Updated: Dec 26, 2025
Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
Published on: December 19, 2018
Development of bivalent triarylalkene- and cyclofenil-derived dual estrogen receptor antagonists and downregulators
Alexandra Knox1, Christina Kalchschmid1, Daniela Schuster2
1Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB - Centrum for Chemistry and Biomedicine, Innsbruck, Austria.
Abstract:
Up to 80% of mammary carcinoma initially exhibit estrogen-dependent growth, which can be treated by aromatase inhibitors or SERMs/SERDs. To increase the options after failure of the hormonal therapy with these drugs, the search for alternatives with a different mode of action to prevent estrogen action is of high relevance. Therefore, this study focused on the inhibition of coactivator recruitment at the estrogen receptor (ER) by targeted attachment of bivalent compounds at the coactivator binding site besides the primary binding at the ligand binding domain. Eight homodimeric 4-[1-(4-hydroxyphenyl)-2-phenyl-1-butenyl]cinnamic acid (GW7604)- or cyclofenilacrylic acid-based ER ligands with diaminoalkane linkers (C2-C5) were synthesized and their effects on the ER subtypes were assessed in vitro. All compounds possessed full antagonistic potency at ERα/β as determined in a transactivation assay. Furthermore, they exerted medium downregulatory effects dependent on the spacer length and did not stimulate the ER expression as observed for 4-hydroxytamoxifen. The cyclofenil-derived dimer with C4 spacer (15b) showed the highest binding affinity to ERα (RBA = 79.2%) and downregulated the ER content in MCF-7 cells with an efficiency of 38% at 1 μM.
Insights
New bivalent estrogen receptor (ER) ligands were synthesized to overcome hormonal therapy resistance in breast cancer. These compounds inhibit coactivator recruitment, offering a novel therapeutic strategy for estrogen-dependent mammary carcinoma.
Area of Science:
- Oncology
- Endocrinology
- Medicinal Chemistry
Background:
- Estrogen receptor (ER) signaling drives significant mammary carcinoma growth.
- Current therapies like aromatase inhibitors and SERMs/SERDs face resistance, necessitating novel treatment strategies.
- Targeting coactivator recruitment offers an alternative mechanism to inhibit ER action.
Purpose of the Study:
- To synthesize and evaluate novel bivalent ER ligands designed to inhibit coactivator recruitment.
- To assess the antagonistic potency and ER downregulatory effects of these compounds in vitro.
- To identify lead compounds for potential use after failure of existing hormonal therapies.
Main Methods:
- Synthesis of eight homodimeric ER ligands based on GW7604 or cyclofenilacrylic acid scaffolds with varying diaminoalkane linkers (C2-C5).
- In vitro assessment of ligand effects on ERα and ERβ subtypes using transactivation assays.
- Evaluation of ER downregulation in MCF-7 cells and relative binding affinity (RBA) to ERα.
Main Results:
- All synthesized compounds demonstrated full antagonistic potency against ERα/β.
- Compounds exhibited medium, spacer length-dependent ER downregulatory effects.
- The cyclofenil-derived dimer with a C4 spacer (15b) displayed the highest ERα binding affinity (RBA = 79.2%) and downregulated ER content by 38% in MCF-7 cells at 1 μM.
Conclusions:
- Novel bivalent ER ligands effectively inhibit ER activity and downregulate ER expression.
- These compounds represent promising alternatives for treating hormone-therapy-resistant breast cancer.
- The cyclofenil-derived dimer with C4 linker shows particular potential for further development.
More Related Videos
06:18An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
05:47In Silico Modeling Method for Computational Aquatic Toxicology of Endocrine Disruptors: A Software-Based Approach Using QSAR Toolbox
Published on: August 28, 2019
Related Concept Videos
01:31Transducer Mechanism: Nuclear Receptors
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
01:29Diels–Alder Reaction Forming Bridged Bicyclic Products: Stereochemistry
02:43E2 Reaction: Stereochemistry and Regiochemistry
When a substrate with two different β hydrogens undergoes an E2 elimination, the presence of a strong base can yield two regioisomeric alkenes. The more-substituted alkene is the major...
01:16Adrenergic Agonists: Chemistry and Structure-Activity Relationship
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
01:17Thermal Electrocyclic Reactions: Stereochemistry
Selection Rules: Thermal Activation
Conjugated systems containing an even number of π-electron pairs undergo a conrotatory ring closure. For example, thermal electrocyclization of (2E,4E)-2,4-hexadiene, a conjugated diene containing two π-electron pairs, gives trans-3,4-dimethylcyclobutene.
01:25Adrenergic Antagonists: Chemistry and Classification of β-Receptor Blockers