title: Discovery of novel quinoline-based estrogen receptor ligands using peptide interaction profiling.
abstract: 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.
authors.affiliation: GlaxoSmithKline Research & Development, Research Triangle Park, North Carolina 27709-3398, USA. william.j.hoekstra@gsk.com
authors.forename: William J
authors.initials: WJ
authors.lastname: Hoekstra
authors.forename: Hari S
authors.initials: HS
authors.lastname: Patel
authors.forename: Xi
authors.initials: X
authors.lastname: Liang
authors.forename: Jean-Baptiste E
authors.initials: JB
authors.lastname: Blanc
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Heyer
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: Marie A
authors.initials: MA
authors.lastname: Iannone
authors.forename: Sue H
authors.initials: SH
authors.lastname: Kadwell
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Miller
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Pearce
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Simmons
authors.forename: Jean
authors.initials: J
authors.lastname: Shearin
mesh_terms: D000469:Alkaline Phosphatase / Q000096:biosynthesis; D001667:Binding, Competitive; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002474:Cell-Free System; D004717:Endometrium / Q000166:cytology; D004790:Enzyme Induction; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008024:Ligands; D008863:Microspheres; D019151:Peptide Library; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D019151:Peptide Library; D011804:Quinolines; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D000469:Alkaline Phosphatase