PMID: 9193132Mar 1, 1997Paper

Design and synthesis of novel tyrosine kinase inhibitors using a pharmacophore model of the ATP-binding site of the EGF-R

Journal de pharmacie de Belgique
Peter TraxlerN B Lydon

Abstract

One of the most promising targets for the rational design of anti-cancer drugs is the family of the EGF-receptor protein tyrosine kinases. Despite the high sequence homology within the ATP-binding region of protein tyrosine and/or serine threonine kinases, ATP-competitive compounds have the potential to be selective inhibitors of protein kinases. Dianilino-phthalimides CGP 52 411 and CGP 53,353 have been identified as potent and ATP-competitive inhibitors of the EGF-R tyrosine kinase with no or only minor activity against a panel of tyrosine and serine/threonine kinases. Using a calculated 3-D computer model of the catalytic domain of the EGF-R-tyrosine kinase together with CGP 52 411 as example of an ATP-competitive inhibitor, a pharmacophore model for ATP-competitive inhibitors in the active site of the EGF-R PTK was developed. With the help of this model, 4-phenylamino-7H-pyrrolo[2,3-d]pyrimidines were then identified as new potent EGF-R PTK inhibitors. In an interactive process, the class of the 4-phenylamino-pyrrolo-pyrimidines was optimized and structure-activity-relationship of a series of derivatives thereof are discussed. In vitro, the most active compounds (CGP 59 326, CGP 60 261, CGP 62 706) inhibited the EGF-R tyros...Continue Reading

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