title: Structure-activity relationships of bisphenol A analogs at estrogen receptors (ERs): discovery of an ERα-selective antagonist.
abstract: Our multi-template approach for drug discovery, focusing on protein targets with similar fold structures, has yielded lead compounds for various targets. We have also shown that a diphenylmethane skeleton can serve as a surrogate for a steroid skeleton. Here, on the basis of those ideas, we hypothesized that the diphenylmethane derivative bisphenol A (BPA) would bind to the ligand-binding domain of estrogen receptors (ERs) in a similar manner to estradiol and act as a steroid surrogate. To test this idea, we synthesized a series of BPA analogs and evaluated their structure-activity relationships, focusing on agonistic/antagonistic activities at ERs and ERα/ERβ subtype selectivity. Among the compounds examined, 18 was found to be a potent ERα-antagonist with high selectivity over ERβ and androgen receptor under our assay conditions. A computational docking study suggested that 18 would bind to the antagonistic conformation of ERα. ERα-selective antagonists, such as 18, are candidate agents for treatment of breast cancer.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Tokyo 113-0032, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Maruyama
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nakamura
authors.forename: Shusuke
authors.initials: S
authors.lastname: Tomoshige
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugita
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Minoru
authors.initials: M
authors.lastname: Ishikawa
mesh_terms: D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D003408:Cresols / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D003408:Cresols; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds