Use of a pharmacophore model for the design of EGFR tyrosine kinase inhibitors: isoflavones and 3-phenyl-4(1H)-quinolones

J Med Chem. 1999 Mar 25;42(6):1018-26. doi: 10.1021/jm980551o.


Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase together with published X-ray crystal data of quercetin (2) in complex with the Hck tyrosine kinase and of deschloroflavopiridol (3b) in complex with CDK2, a putative binding mode of the isoflavone genistein (1) was proposed. Then, based on literature data suggesting that a salicylic acid function, which is represented by the 5-hydroxy-4-keto motif in 1, could serve as a pharmacophore replacement of a pyrimidine ring, superposition of 1 onto the potent EGFR tyrosine kinase inhibitor 4-(3'-chlorophenylamino)-6, 7-dimethoxyquinazoline (4) led to 3'-chloro-5,7-dihydroxyisoflavone (6) as a target structure which in fact was 10 times more potent than 1. The putative binding mode of 6 suggests a sulfur-aromatic interaction of the m-chlorophenyl moiety with Cys 773 in the "sugar pocket" of the EGFR kinase model. Replacement of the oxygen in the chromenone ring of 6 by a nitrogen atom further improved the inhibitory activity against the EGFR kinase. With IC50 values of 38 and 8 nM, respectively, the quinolones 11 and 12 were the most potent compounds of the series. N-Alkylation of 11 did not further improve enzyme inhibitory activity but led to derivatives with cellular activity in the lower micromolar range.

MeSH terms

  • Animals
  • Binding Sites
  • Cell Division / drug effects
  • Cell Line
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • ErbB Receptors / antagonists & inhibitors*
  • Genistein / metabolism
  • Isoflavones / chemical synthesis*
  • Isoflavones / chemistry
  • Isoflavones / pharmacology
  • Mice
  • Models, Molecular
  • Phosphorylation
  • Protein Binding
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Quinolones / chemical synthesis*
  • Quinolones / chemistry
  • Quinolones / pharmacology
  • Structure-Activity Relationship


  • 3'-chloro-5,7-dihydroxyisoflavone
  • Enzyme Inhibitors
  • Isoflavones
  • Quinolones
  • Genistein
  • ErbB Receptors
  • Protein-Tyrosine Kinases