title: Erythropoietin mimetics derived from solution phase combinatorial libraries.
abstract: The erythropoietin receptor (EPOr) is activated by ligand-induced homodimerization, which leads to the proliferation and differentiation of erythroid progenitors. Through the screening of combinatorial libraries of dimeric iminodiacetic acid diamides, novel small molecule binders of EPOr were identified in a protein binding assay. Evaluation of a series of analogues led to optimization of binding subunits, and these were utilized in the synthesis of higher order dimer, trimer, and tetramer libraries. Several of the most active EPOr binders were found to be partial agonists and induced concentration-dependent proliferation of an EPO-dependent cell line (UT-7/EPO) while having no effect on a cell line lacking the EPOr (FDC-P1). An additional compound library, based on a symmetrical isoindoline-5,6-dicarboxylic acid template and including the optimized binding subunits, was synthesized and screened leading to the identification of additional EPO mimetics.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Goldberg
authors.forename: Qing
authors.initials: Q
authors.lastname: Jin
authors.forename: Yves
authors.initials: Y
authors.lastname: Ambroise
authors.forename: Shigeki
authors.initials: S
authors.lastname: Satoh
authors.forename: Joel
authors.initials: J
authors.lastname: Desharnais
authors.forename: Kevin
authors.initials: K
authors.lastname: Capps
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D002455:Cell Division / Q000502:physiology; D020650:Combinatorial Chemistry Techniques; D003998:Dicarboxylic Acids / Q000737:chemistry* / Q000378:metabolism*; D004921:Erythropoietin / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007098:Imino Acids / Q000737:chemistry* / Q000378:metabolism*; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism*; D018716:Molecular Mimicry; D017467:Receptors, Erythropoietin / Q000378:metabolism* / Q000502:physiology; D012996:Solutions; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D003998:Dicarboxylic Acids; D007098:Imino Acids; D007211:Indoles; D017467:Receptors, Erythropoietin; D012996:Solutions; D004921:Erythropoietin; C057812:indoline; C008109:iminodiacetic acid