Erythropoietin mimetics derived from solution phase combinatorial libraries

J Am Chem Soc. 2002 Jan 30;124(4):544-55. doi: 10.1021/ja0118789.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Division / physiology
  • Combinatorial Chemistry Techniques
  • Dicarboxylic Acids / chemistry*
  • Dicarboxylic Acids / metabolism*
  • Erythropoietin / metabolism*
  • Erythropoietin / physiology
  • Humans
  • Imino Acids / chemistry*
  • Imino Acids / metabolism*
  • Indoles / chemistry*
  • Indoles / metabolism*
  • Molecular Mimicry*
  • Receptors, Erythropoietin / metabolism*
  • Receptors, Erythropoietin / physiology
  • Solutions
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Dicarboxylic Acids
  • Imino Acids
  • Indoles
  • Receptors, Erythropoietin
  • Solutions
  • Erythropoietin
  • indoline
  • iminodiacetic acid