title: A structure-guided approach to an orthogonal estrogen-receptor-based gene switch activated by ligands suitable for in vivo studies.
abstract: A strategy to obtain a fully orthogonal estrogen-receptor-based gene switch responsive to molecules with acceptable pharmacological properties is presented. From a series of tetrahydrofluorenones active on the wild-type estrogen receptor (ER) an inactive analogue is chosen as a new lead compound. Coevolution of receptor mutants and ligands leads to an ER-based gene switch suitable for studies in animal models.
authors.affiliation: IRBM (Merck Research Laboratories Rome), Via Pontina km 30,600, 00040 Pomezia, Rome, Italy. olaf_kinzel@merck.com
authors.forename: Olaf
authors.initials: O
authors.lastname: Kinzel
authors.forename: Daniela
authors.initials: D
authors.lastname: Fattori
authors.forename: Ester
authors.initials: E
authors.lastname: Muraglia
authors.forename: Paola
authors.initials: P
authors.lastname: Gallinari
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Nardi
authors.forename: Chantal
authors.initials: C
authors.lastname: Paolini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Roscilli
authors.forename: Carlo
authors.initials: C
authors.lastname: Toniatti
authors.forename: Odalys
authors.initials: O
authors.lastname: Gonzalez Paz
authors.forename: Ralph
authors.initials: R
authors.lastname: Laufer
authors.forename: Armin
authors.initials: A
authors.lastname: Lahm
authors.forename: Anna
authors.initials: A
authors.lastname: Tramontano
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cortese
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.forename: Gennaro
authors.initials: G
authors.lastname: Ciliberto
authors.forename: Uwe
authors.initials: U
authors.lastname: Koch
mesh_terms: D001665:Binding Sites; D004958:Estradiol / Q000737:chemistry; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000235:genetics; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000235:genetics; D005449:Fluorenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005449:Fluorenes; D008024:Ligands; D011960:Receptors, Estrogen; D004958:Estradiol