A structure-guided approach to an orthogonal estrogen-receptor-based gene switch activated by ligands suitable for in vivo studies.
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.
Kinzel
Olaf
O
IRBM (Merck Research Laboratories Rome), Via Pontina km 30,600, 00040 Pomezia, Rome, Italy. olaf_kinzel@merck.com
Fattori
Daniela
D
Muraglia
Ester
E
Gallinari
Paola
P
Nardi
Maria Chiara
MC
Paolini
Chantal
C
Roscilli
Giuseppe
G
Toniatti
Carlo
C
Gonzalez Paz
Odalys
O
Laufer
Ralph
R
Lahm
Armin
A
Tramontano
Anna
A
Cortese
Riccardo
R
De Francesco
Raffaele
R
Ciliberto
Gennaro
G
Koch
Uwe
U
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
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005449:Fluorenes; D008024:Ligands; D011960:Receptors, Estrogen; D004958:Estradiol