The rationale and strategy used to develop a series of highly potent, irreversible, inhibitors of the epidermal growth factor receptor family of tyrosine kinases.

The Epidermal Growth Factor receptor (EGFr) was one of the first oncogenes identified, and it, or its ligands Epidermal Growth Factor (EGF) and Transforming Growth Factor a (TGFa) are overexpressed in most clinical tumours. As EGF and TGFa are potent mitogens, it appeared that inhibition of EGFr signaling would be a viable anti-proliferative strategy. Screening found several classes of EGFr inhibitor, one of which, the indolinethiones was developed. The SAR, in common with that of other first generation tyrosine kinase (TK) inhibitors was flat, and potency was poor. Rescreening in presence of a thiol, to remove chemically reactive species, identified only two leads, a pyridopyrimidine and a quinazoline. These were developed into a very broad class of EGFr inhibitors, with great potency and selectivity for EGFr, but poor physicochemical properties, and little if any in vivo anti-tumour activity. Meanwhile the complex role of other members of the EGFr TK family in oncogenesis, was becoming apparent, suggesting that the whole EGFr family should be inhibited. The difficulty of finding potent compounds with acceptable pharmacokinetics also suggested that irreversible inhibitors of the TK might produce better in vivo profiles. Modeling suggested that the unusual Cys773 residue might be reached from the 6/7-positions of quinazoline and pyridopyrimidine inhibitors. Inhibitors with acrylamides at these positions proved to be irreversible alkylating agents for both EGFr and erbB-2 with cellular inhibitory activities in the low nanomolar range, and very potent in vivo antitumour activity. Optimized inhibitors had exceptionally potent oral antitumour activity, with negligible cytotoxicity.