A structure-guided approach to an orthogonal estrogen-receptor-based gene switch activated by ligands suitable for in vivo studies

  • J Med Chem. 2006 Sep 7;49(18):5404-7. doi: 10.1021/jm060516e.
Olaf Kinzel  1 ,  Daniela Fattori ,  Ester Muraglia ,  Paola Gallinari ,  Maria Chiara Nardi ,  Chantal Paolini ,  Giuseppe Roscilli ,  Carlo Toniatti ,  Odalys Gonzalez Paz ,  Ralph Laufer ,  Armin Lahm ,  Anna Tramontano ,  Riccardo Cortese ,  Raffaele De Francesco ,  Gennaro Ciliberto ,  Uwe Koch
Affiliations
  • 1. IRBM (Merck Research Laboratories Rome), Via Pontina km 30,600, 00040 Pomezia, Rome, Italy. [email protected]
PMID: 16942012 DOI: 10.1021/jm060516e
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.

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