Amphipathic benzenes are designed inhibitors of the estrogen receptor alpha/steroid receptor coactivator interaction.
We report here on the design, synthesis, and evaluation of small molecule inhibitors of the interaction between a steroid receptor coactivator and estrogen receptor alpha. These inhibitors are based upon an amphipathic benzene scaffold whose hydrophobic face mimics the leucine-rich alpha-helical consensus sequence on the steroid receptor coactivators that interacts with a shallow groove on estrogen receptor alpha. Several of these molecules are among the most potent inhibitors of this interaction described to date and are active at low micromolar concentrations in both in vitro models of estrogen receptor action and in cell-based assays of estrogen receptor-mediated coactivator interaction and transcription.
Gunther
Jillian R
JR
Moore
Terry W
TW
Collins
Margaret L
ML
Katzenellenbogen
John A
JA
D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D031541:Fluorescence Resonance Energy Transfer; D017930:Genes, Reporter; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000235:genetics; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D010957:Plasmids; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D020798:Two-Hybrid System Techniques
D001555:Benzene Derivatives; D047628:Estrogen Receptor alpha; D008024:Ligands; D011743:Pyrimidines; D015534:Trans-Activators; D014157:Transcription Factors; D008156:Luciferases; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538866:NCOA3 protein, human; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3