Blocking estrogen signaling after the hormone: pyrimidine-core inhibitors of estrogen receptor-coactivator binding

J Med Chem. 2008 Oct 23;51(20):6512-30. doi: 10.1021/jm800698b. Epub 2008 Sep 12.


As an alternative approach to blocking estrogen action, we have developed small molecules that directly disrupt the key estrogen receptor (ER)/coactivator interaction necessary for gene activation. The more direct, protein-protein nature of this disruption might be effective even in hormone-refractory breast cancer. We have synthesized a pyrimidine-core library of moderate size, members of which act as alpha-helix mimics to block the ERalpha/coactivator interaction. Structure-activity relationships have been explored with various C-, N-, O-, and S-substituents on the pyrimidine core. Time-resolved fluorescence resonance energy transfer and cell-based reporter gene assays show that the most active members inhibit the ERalpha/steroid receptor coactivator interaction with K i's in the low micromolar range. Through these studies, we have obtained a refined pharmacophore model for activity in this pyrimidine series. Furthermore, the favorable activities of several of these compounds support the feasibility that this coactivator binding inhibition mechanism for blocking estrogen action might provide a potential alternative approach to endocrine therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Amines / chemistry
  • Cell Line
  • Combinatorial Chemistry Techniques
  • Drug Design
  • Estrogens / metabolism*
  • Fluorescence Resonance Energy Transfer
  • Genes, Reporter / genetics
  • Humans
  • Ligands
  • Methylation
  • Models, Molecular
  • Molecular Structure
  • Phenol / chemistry
  • Protein Binding
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Receptors, Estrogen / antagonists & inhibitors*
  • Receptors, Estrogen / chemistry
  • Receptors, Estrogen / metabolism*
  • Signal Transduction / drug effects*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transcription, Genetic / genetics


  • Amines
  • Estrogens
  • Ligands
  • Pyrimidines
  • Receptors, Estrogen
  • Phenol
  • pyrimidine