Nonsteroidal estrogen receptor isoform-selective biphenyls

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.