Related Experiment Video

Updated: Oct 20, 2025

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
09:07

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay

Published on: December 19, 2018

6.5K

Benzothiophene derivatives as selective estrogen receptor covalent antagonists: Design, synthesis and anti-ERα

Chengfeng Bai1, Shuangjie Wu1, Shengnan Ren1

  • 1State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

Bioorganic & Medicinal Chemistry
|September 12, 2021
PubMed

Insights

Researchers developed novel covalent antagonists targeting estrogen receptor alpha (ERα) to combat endocrine-resistant breast cancer. Compound 19d shows potent anti-cancer activity without harmful side effects, offering a promising new therapeutic strategy.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Molecular Pharmacology

Background:

  • Estrogen receptor alpha (ERα) is a key target in ER+ breast cancer treatment.
  • Endocrine resistance, often developing with therapies like Tamoxifen, affects approximately 50% of patients.
  • Selective estrogen receptor covalent antagonists (SERCAs) offer a potential therapeutic alternative.

Purpose of the Study:

  • To design, synthesize, and evaluate novel 6-OH-benzothiophene (BT) derivatives as ERα covalent antagonists.
  • To identify compounds with potent antiproliferative activity against ER+ breast cancer cells.
  • To investigate the binding mode and specificity of the lead compound.

Main Methods:

  • Synthesis of novel 6-OH-benzothiophene derivatives based on Raloxifene.
  • Biological evaluation of antiproliferative efficacy in ER+ breast cancer cells.
  • Assessment of agonistic activity in endometrial cells.
  • Molecular docking simulations to elucidate binding interactions.

Main Results:

  • Compound 19d demonstrated potent antagonistic activity against ERα in ER+ breast cancer cells.
  • Compound 19d exhibited no agonistic activity in endometrial cells, indicating specificity.
  • Docking simulations revealed that 19d covalently binds to cysteine residue 530 in ERα helix H11.

Conclusions:

  • Novel BT derivatives were successfully designed and synthesized as potential SERCAs.
  • Compound 19d represents a promising therapeutic candidate for endocrine-resistant ER+ breast cancer.
  • The covalent binding mechanism of 19d to ERα was elucidated, supporting its antagonistic function.
Keywords:
Breast cancerCovalent antagonistDrug designEstrogen receptorResistance

More Related Videos

Screening for Phytoestrogens using a Cell-based Estrogen Receptor β Reporter Assay06:07

Screening for Phytoestrogens using a Cell-based Estrogen Receptor β Reporter Assay

Published on: June 7, 2020

5.0K
In Silico Modeling Method for Computational Aquatic Toxicology of Endocrine Disruptors: A Software-Based Approach Using QSAR Toolbox05:47

In Silico Modeling Method for Computational Aquatic Toxicology of Endocrine Disruptors: A Software-Based Approach Using QSAR Toolbox

Published on: August 28, 2019

14.2K

Related Concept Videos

Adrenergic Agonists: Chemistry and Structure-Activity Relationship01:16

Adrenergic Agonists: Chemistry and Structure-Activity Relationship

Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
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...
3.5K
Adrenergic Antagonists: Chemistry and Classification of ɑ-Receptor Blockers01:17

Adrenergic Antagonists: Chemistry and Classification of ɑ-Receptor Blockers

Adrenergic antagonists, or sympatholytics, inhibit adrenoceptor activation driven by catecholamines or agonists. Based on their adrenoceptor specificity, adrenergic blockers can be categorized into two primary groups: α-adrenergic blockers (α-blockers) and β-adrenergic blockers (β-blockers). α-blockers interact with α1 and α2 subtypes of α-adrenoceptors.
Nonselective α-blockers: Nonselective α-blockers contain haloalkylamine or imidazoline...
1.2K
Structure-Activity Relationships and Drug Design01:28

Structure-Activity Relationships and Drug Design

Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
1.2K
Adrenergic Antagonists: Chemistry and Classification of β-Receptor Blockers01:25

Adrenergic Antagonists: Chemistry and Classification of β-Receptor Blockers

β-adrenergic antagonists, or β-blockers, modulate the sympathetic nervous system by targeting β-adrenoceptors and inhibiting catecholamine-mediated sympathetic responses. β-blockers differ in their adrenoceptor subtype affinity, lipophilicity, and α-blocking capabilities. The history of β-blocker development began with the prototype, dichloroisoprenaline, which exhibited partial agonist activity. As a result, propranolol was developed as a pure antagonist but...
930
Directing and Steric Effects in Disubstituted Benzene Derivatives01:18

Directing and Steric Effects in Disubstituted Benzene Derivatives

When disubstituted benzenes undergo electrophilic substitution, the product distribution depends on the directing effect of both substituents. When the directing effects of both substituents reinforce each other, a single product is obtained. For example, bromination of p-nitrotoluene occurs ortho to the methyl group and meta to the nitro group, which is the same position, resulting in a single product. However, if the directing effects of the two groups oppose each other, the...
3.4K
Transducer Mechanism: Nuclear Receptors01:31

Transducer Mechanism: Nuclear Receptors

Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
1.9K