Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control

J Med Chem. 2009 Oct 22;52(20):6362-8. doi: 10.1021/jm900630q.


The Ras/Raf/MEK/ERK signal transduction, an oncogenic pathway implicated in a variety of human cancers, is a key target in anticancer drug design. A novel series of pyrimidylpyrrole ERK inhibitors has been identified. Discovery of a conformational change for lead compound 2, when bound to ERK2 relative to antitarget GSK3, enabled structure-guided selectivity optimization, which led to the discovery of 11e, a potent, selective, and orally bioavailable inhibitor of ERK.

MeSH terms

  • Drug Design*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Extracellular Signal-Regulated MAP Kinases / chemistry
  • Models, Molecular
  • Molecular Conformation*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology*
  • Substrate Specificity


  • Protein Kinase Inhibitors
  • Pyrroles
  • Extracellular Signal-Regulated MAP Kinases

Associated data

  • PDB/3I4B
  • PDB/3I5Z
  • PDB/3I60