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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
Structure-Activity Relationship Study of Tris-Benzamides as Estrogen Receptor Coregulator Binding Modulators
Tae-Kyung Lee1, Kara Kassees1, Chia-Yuan Chen1
1Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, Texas 75080, United States.
Abstract:
Estrogen receptor coregulator binding modulators (ERXs) are a novel class of molecules targeting the interaction between estrogen receptor α (ERα) and its coregulator proteins, which has proven to be an attractive strategy for overcoming endocrine resistance in breast cancer. We previously reported ERX-11, an orally bioavailable tris-benzamide, that demonstrated promising antitumor activity against ERα-positive breast cancer cells. To comprehend the significance of the substituents in ERX-11, we carried out structure-activity relationship studies. In addition, we introduced additional alkyl substituents at either the N- or C-terminus to improve binding affinity and biological activity. Further optimization guided by conformational restriction led to the identification of a trans-4-phenylcyclcohexyl group at the C-terminus (18h), resulting in a greater than 10-fold increase in binding affinity and cell growth inhibition potency compared to ERX-11. Tris-benzamide 18h disrupted the ERα-coregulator interaction and inhibited the ERα-mediated transcriptional activity. It demonstrated strong antiproliferative activity on ERα-positive breast cancer cells both in vitro and in vivo, offering a promising potential as a therapeutic candidate for treating ERα-positive breast cancer.
Insights
Estrogen receptor coregulator binding modulators (ERXs) offer a new approach to overcoming endocrine resistance in breast cancer. Optimized ERX compound 18h shows significantly enhanced binding affinity and potent antitumor activity against ERα-positive breast cancer.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Pharmacology
Background:
- Estrogen receptor coregulator binding modulators (ERXs) target the ERα-coregulator interaction, a key strategy for overcoming endocrine resistance in breast cancer.
- Previous work identified ERX-11, an orally bioavailable tris-benzamide with antitumor activity against ERα-positive breast cancer cells.
Purpose of the Study:
- To understand the role of substituents in ERX-11 through structure-activity relationship (SAR) studies.
- To optimize ERX compounds for improved binding affinity and biological activity against ERα-positive breast cancer.
Main Methods:
- Conducted SAR studies on ERX-11, introducing alkyl substituents at N- and C-termini.
- Utilized conformational restriction to guide optimization, leading to compound 18h with a trans-4-phenylcyclohexyl group.
- Assessed binding affinity, cell growth inhibition, ERα-coregulator interaction disruption, and ERα-mediated transcriptional activity.
Main Results:
- Compound 18h demonstrated a >10-fold increase in binding affinity and cell growth inhibition potency compared to ERX-11.
- 18h effectively disrupted the ERα-coregulator interaction and inhibited ERα-mediated transcriptional activity.
- Significant antiproliferative activity of 18h was observed in ERα-positive breast cancer cells both in vitro and in vivo.
Conclusions:
- Tris-benzamide 18h represents a highly optimized ERX with potent anticancer effects.
- Compound 18h shows significant therapeutic potential as a candidate for treating ERα-positive breast cancer, particularly in endocrine-resistant cases.
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