Nonsteroidal estrogen receptor isoform-selective biphenyls

Estrogen receptor (ER) has been a therapeutic target to treat ER-positive breast cancer, most notably by agents known as selective estrogen receptor modulators (SERMs). However, resistance and severe adverse effects of known drugs gave impetus to the search for newer agents with better therapeutic profile. ER and ER are two isoforms sharing 56% identity and having different physiological functions and expressions in various tissues. Only two residues differ in the active sites of the two isoforms motivating us to design isoform-selective ligands. Guided by computational docking and molecular dynamics simulations, we have designed, synthesized, and tested, substituted biphenyl-2,6-diethanones and their derivatives as potential agents targeting ER. Four of the molecules synthesized exhibited preferential cytotoxicity in ER+ cell line (MCF-7) compared to ER+ cell line (MDA-MB-231). Molecular dynamics (MD) in combination with molecular mechanics-generalized Born surface area (MM-GBSA) methods could account for binding selectivity. Further cotreatment and E-screen studies with known ER ligandsestradiol (E-2) and tamoxifen (Tam)indicated isoform-selective anti-estrogenicity in ER+ cell line which might be ER-mediated. ER siRNA silencing experiments further confirmed the ER selective nature of ligands.