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Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
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Structure-Activity Relationship Study of Tris-Benzamides as Estrogen Receptor Coregulator Binding Modulators.

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|July 18, 2024
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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.

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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.