title: Discovering small-molecule estrogen receptor α/coactivator binding inhibitors: high-throughput screening, ligand development, and models for enhanced potency.
abstract: Small molecules, namely coactivator binding inhibitors (CBIs), that block estrogen signaling by directly inhibiting the interaction of the estrogen receptor (ER) with coactivator proteins act in a fundamentally different way to traditional antagonists, which displace the endogenous ligand estradiol. To complement our prior efforts at CBI discovery by de novo design, we used high-throughput screening (HTS) to identify CBIs of novel structure and subsequently investigated two HTS hits by analogue synthesis, finding many compounds with low micromolar potencies in cell-based reporter gene assays. We examined structure-activity trends in both series, using induced-fit computational docking to propose binding poses for these molecules in the coactivator binding groove. Analysis of the structure of the ER-steroid receptor coactivator (SRC) complex suggests that all four hydrophobic residues within the SRC nuclear receptor box sequence are important binding elements. Thus, insufficient water displacement upon binding of the smaller CBIs in the expansive complexation site may be limiting the potency of the compounds in these series, which suggests that higher potency CBIs might be found by screening compound libraries enriched with larger molecules.
authors.affiliation: Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA. asun2@emory.edu
authors.forename: Aiming
authors.initials: A
authors.lastname: Sun
authors.forename: Terry W
authors.initials: TW
authors.lastname: Moore
authors.forename: Jillian R
authors.initials: JR
authors.lastname: Gunther
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Kim
authors.forename: Eric
authors.initials: E
authors.lastname: Rhoden
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D001665:Binding Sites; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D056918:Nuclear Receptor Coactivators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D008024:Ligands; D056918:Nuclear Receptor Coactivators; D008156:Luciferases