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Discovery of Novel Quinoline-Based Estrogen Receptor Ligands Using Peptide Interaction Profiling

2004; American Chemical Society; Volume: 48; Issue: 6 Linguagem: Inglês

10.1021/jm040154f

1520-4804

William J. Hoekstra, Hari S. Patel, Xi Liang, Jean-Baptiste E. Blanc, Dennis Heyer, Timothy M. Willson, Marie A. Iannone, Sue H. Kadwell, Lisa A. Miller, Kenneth H. Pearce, Catherine A. Simmons, Jean Shearin,

Chemical Synthesis and Analysis

Traditional approaches to discovery of selective estrogen receptor modulators (SERMs) have relied on ER binding and cell-based estrogen response element-driven assays to identify compounds that are osteoprotective but nonproliferative in breast and uterine tissues. To discover new classes of potential SERMs, we have employed a cell-free microsphere-based binding assay to rapidly characterize ERalpha interactions with conformation-sensing cofactor or phage display peptides. Peptide profiles of constrained triarenes were compared to known proliferative and nonproliferative ER ligands to discover potent quinoline-based ligands with minimal Ishikawa cell stimulation.