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

• Published in: Journal of medicinal chemistry 2005-03, Vol.48 (6), p.2243-2247
• Main Authors: Hoekstra, William J, Patel, Hari S, Liang, Xi, Blanc, Jean-Baptiste E, Heyer, Dennis O, Willson, Timothy M, Iannone, Marie A, Kadwell, Sue H, Miller, Lisa A, Pearce, Kenneth H, Simmons, Catherine A, Shearin, Jean
• Format: Article
• Language: English
• Subjects: Alkaline Phosphatase - biosynthesis; Binding, Competitive; Biological and medical sciences; Cell Line; Cell Proliferation - drug effects; Cell-Free System; Endometrium - cytology; Enzyme Induction; Estrogen Receptor alpha - drug effects; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - drug effects; Estrogen Receptor beta - metabolism; Female; Hormones. Endocrine system; Humans; Ligands; Medical sciences; Microspheres; Peptide Library; Pharmacology. Drug treatments; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Receptors, Estrogen - drug effects; Receptors, Estrogen - metabolism; Selective Estrogen Receptor Modulators - chemical synthesis; Selective Estrogen Receptor Modulators - chemistry; Selective Estrogen Receptor Modulators - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm040154f

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 ERα 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.