Erythropoietin Mimetics Derived from Solution Phase Combinatorial Libraries

详细信息    查看全文

• 作者：Joel Goldberg ; Qing Jin ; Yves Ambroise ; Shigeki Satoh ; Joel Desharnais ; Kevin Capps ; and Dale L. Boger
• 刊名：Journal of the American Chemical Society
• 出版年：2002
• 出版时间：January 30, 2002
• 年：2002
• 卷：124
• 期：4
• 页码：544 - 555
• 全文大小：452K
• 年卷期：v.124,no.4(January 30, 2002)
• ISSN：1520-5126

文摘

The erythropoietin receptor (EPOr) is activated by ligand-induced homodimerization, which leadsto the proliferation and differentiation of erythroid progenitors. Through the screening of combinatorial librariesof dimeric iminodiacetic acid diamides, novel small molecule binders of EPOr were identified in a proteinbinding assay. Evaluation of a series of analogues led to optimization of binding subunits, and these wereutilized in the synthesis of higher order dimer, trimer, and tetramer libraries. Several of the most activeEPOr binders were found to be partial agonists and induced concentration-dependent proliferation of anEPO-dependent cell line (UT-7/EPO) while having no effect on a cell line lacking the EPOr (FDC-P1). Anadditional compound library, based on a symmetrical isoindoline-5,6-dicarboxylic acid template and includingthe optimized binding subunits, was synthesized and screened leading to the identification of additionalEPO mimetics.