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Nonsteroidal estrogen receptor isoform-selective biphenyls

Seema Bhatnagar1, Anjali Soni2, Swati Kaushik1,3

  • 1Amity Institute of Biotechnology, Amity University, Noida, India.

Chemical Biology & Drug Design
|October 21, 2017
PubMed

Insights

Researchers developed novel ERα-selective compounds to combat breast cancer resistance. These new agents show preferential cytotoxicity and anti-estrogenic effects in ERα-positive cells, offering a promising therapeutic avenue.

Area of Science:

  • Medicinal Chemistry
  • Molecular Pharmacology
  • Computational Chemistry

Background:

  • Estrogen receptor (ER) targeted therapies, including SERMs, are crucial for ER-positive breast cancer.
  • Drug resistance and adverse effects necessitate novel therapeutic agents.
  • ERα and ERβ isoforms have distinct functions, making isoform-selective targeting desirable.

Purpose of the Study:

  • To design and synthesize novel isoform-selective ERα ligands.
  • To evaluate the therapeutic potential of these compounds against ER-positive breast cancer.

Main Methods:

  • Computational docking and molecular dynamics simulations guided ligand design.
  • Synthesis and in vitro testing of substituted biphenyl-2,6-diethanones.
  • Cytotoxicity assays, E-screen assays, and ERα siRNA silencing were performed.

Main Results:

  • Four synthesized compounds showed preferential cytotoxicity in ERα+ MCF-7 cells over ERβ+ MDA-MB-231 cells.
  • Molecular dynamics and MM-GBSA methods explained binding selectivity.
  • Compounds demonstrated isoform-selective anti-estrogenicity in ERα+ cells, confirmed by siRNA studies.

Conclusions:

  • Novel biphenyl-2,6-diethanone derivatives exhibit promising ERα selectivity.
  • These compounds represent potential new therapeutic agents for ER-positive breast cancer with improved profiles.
Keywords:
Biphenyl-2,6-diethanoneDocking and scoringEstrogen receptorMolecular dynamicssiRNA silencing

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