TY - JOUR T1 - Differential Response of Estrogen Receptors α and β to SP500263, a Novel Potent Selective Estrogen Receptor Modulator JF - Molecular Pharmacology JO - Mol Pharmacol SP - 562 LP - 568 DO - 10.1124/mol.61.3.562 VL - 61 IS - 3 AU - Helen Brady AU - Mary Doubleday AU - Leah M. Gayo-Fung AU - Matt Hickman AU - Sak Khammungkhune AU - Adam Kois AU - Stephanie Lipps AU - Steve Pierce AU - Normand Richard AU - Graciella Shevlin AU - May Kung Sutherland AU - David W. Anderson AU - Shripad S. Bhagwat AU - Bernd Stein Y1 - 2002/03/01 UR - http://molpharm.aspetjournals.org/content/61/3/562.abstract N2 - We determined the differential response of a novel SERM, SP500263, on estrogen receptor (ER) α and the more recently cloned ER-β. Because of the high homology of amino acid residues in the ligand-binding domain of ER-α and ER-β, we were not surprised to find that SP500263 binds to both ERs equally well. In contrast, SP500263 acts as a strong estrogen agonist in a strictly ER-α–specific manner in U2OS osteosarcoma cell lines blocking the production of interleukin (IL) 6 and granulocyte macrophage colony-stimulating factor. SP500263 also blocked IL-6 production in primary bone cells. The mechanism of this inhibition is different from the classic estrogen stimulation involving an estrogen response element (ERE). SP500263 does not activate gene expression through an ERE. In contrast to the results observed in U2OS cells, SP500263 acts as a strong estrogen antagonist in an MCF-7 breast cancer proliferation assay. Therefore, SP500263 is a member of a series of next-generation SERMs with functional selectivity toward ER-α and a mixed agonist/antagonist profile in a bone cell assay versus a breast cancer assay. The panel of assays described herein allow for the development of receptor-specific ligands that may be further developed into novel pharmaceuticals with an improved profile for the treatments of osteoporosis and breast cancer. ER -