Erythropoietin mimetics derived from solution phase combinatorial libraries.
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.
Goldberg
Joel
J
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Jin
Qing
Q
Ambroise
Yves
Y
Satoh
Shigeki
S
Desharnais
Joel
J
Capps
Kevin
K
Boger
Dale L
DL
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
D003998:Dicarboxylic Acids; D007098:Imino Acids; D007211:Indoles; D017467:Receptors, Erythropoietin; D012996:Solutions; D004921:Erythropoietin; C057812:indoline; C008109:iminodiacetic acid