Tyrosine kinase inhibitors. 15. 4-(phenylamino)quinazoline and 4-(phenylamino)pyrido[d] pyrimidine acrylamides as irreversible inhibitors of the ATP binding site of the epidermal growth factor receptor

A series of 6- and 7-acrylamide derivatives of the 4-(phenylamino)quinazoli ne and -pyridopyrimidine classes of epidermal growth factor receptor (EGFR) inhibitors were prepared from the corresponding amino compounds by reactio n with either acryloyl chloride/base or acrylic acid/1-(3-dimethylaminoprop yl)-3-ethylcarbodiimide hydrochloride. All of the 6-acrylamides, but only t he parent quinazoline 7-acrylamide, were irreversible inhibitors of the iso lated enzyme, confirming that the former are better-positioned, when bound to the enzyme, to react with the critical cysteine-773. Quinazoline, pyrido [3,4-d]pyrimidine, and pyrido[3,2-d]pyrimidine 6-acrylamides were all irrev ersible inhibitors and showed similar high potencies in the enzyme assay (l ikely due to titration of the available enzyme). However the pyrido[3,2-d]p yrimidine analogues were 2-6-fold less potent than the others in a cellular autophosphorylation assay for EGFR in A431 cells. The quinazolines were ge nerally less potent overall toward inhibition of heregulin-stimulated autop hosphorylation of erbB2 (in MDA-MB-453-cells), whereas the pyridopyrimidine s were equipotent. Selected compounds were evaluated in A431 epidermoid and H125 non-small-cell lung cancer human tumor xenografts. The compounds show ed better activity when given orally than intraperitoneally. All showed sig nificant tumor growth inhibition (stasis) over a dose range. The poor aqueo us solubility of the compounds was a drawback, requiring formulation as fin e particulate emulsions.