title: Synthesis and biological evaluation of guanylhydrazone coactivator binding inhibitors for the estrogen receptor.
abstract: Most patients with hormone-responsive breast cancer eventually develop resistance to traditional antiestrogens such as tamoxifen, and this has become a major obstacle in their treatment. We prepared and characterized the activity of a series of 16 guanylhydrazone small molecules that are designed to block estrogen receptor (ER) activity through a non-traditional mechanism, by directly interfering with coactivator binding to agonist-liganded ER. The inhibitory activity of these compounds was determined in cell-based transcription assays using ER-responsive reporter gene and mammalian two-hybrid assays. Several of the compounds gave IC(50) values in the low micromolar range. Two secondary assays were used to confirm that these compounds were acting through the proposed non-traditional mode of estrogen inhibitory action and not as conventional antagonists at the ligand binding site.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: LaFrate
authors.forename: Jillian R
authors.initials: JR
authors.lastname: Gunther
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D001665:Binding Sites; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008024:Ligands; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D004965:Estrogen Antagonists; D006835:Hydrazones; D008024:Ligands; D011960:Receptors, Estrogen