Discovery of EGFR selective 4,6-disubstituted pyrimidines from a combinatorial kinase-directed heterocycle library

J Am Chem Soc. 2006 Feb 22;128(7):2182-3. doi: 10.1021/ja0567485.


The epidermal growth factor receptor (EGFR) tyrosine kinase was one of the first receptor tyrosine kinases to be targeted for drug development by the pharmaceutical industry due to its ubiquitous overexpression in a variety of tumors. Despite the validation of several quinazoline-based scaffolds in the clinic, there is a dearth of alternative chemical structure classes that are capable of inhibiting EGFR kinase activity selectively. Here we describe the discovery of potent and highly selective 4,6-disubstituted pyrimidine inhibitors of enzymatic and cellular EGFR activity and provide an explanation for their exceptional degree of kinase selectivity.

MeSH terms

  • Combinatorial Chemistry Techniques / methods
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / chemistry*
  • ErbB Receptors / metabolism
  • Gefitinib
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Phosphorylation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Structure, Tertiary
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Quinazolines / chemistry
  • Quinazolines / metabolism
  • Quinazolines / pharmacology
  • Structure-Activity Relationship


  • Protein Kinase Inhibitors
  • Pyrimidines
  • Quinazolines
  • ErbB Receptors
  • Gefitinib