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

Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase together with publishe d X-ray crystal data of quercetin (2) in complex with the lick tyrosine kin ase and of deschloroflavopiridol (3b) in complex with CDK2, a putative bind ing mode of the isoflavone genistein (1) was proposed. Then, based on liter ature data suggesting that a salicylic acid function, which is represented by the 5-hydroxy-4-keto motif in I, could serve as a pharmacophore replacem ent 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-clibydroxyisoflavone (fi) as a target structure which in f act was 10 times more potent than 1. The putative binding mode of 6 suggest s a sulfur-aromatic interaction of the m-chlorophenyl moiety with Cys 773 i n 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 inhibitor y activity against the EGFR kinase. With IC50 values of 38 and 8 nM, respec tively, the quinolones 11 and 12 were the most potent compounds of the seri es. N-Alkylation of II did not further improve enzyme inhibitory activity b ut; led to derivatives with cellular activity in the lower micromolar range .