The authors developed seven potent quinazoline and pyrido-pyrimidine small molecules that are dual inhibitors of HER-2 and EGFR tyrosine kinases. These molecules exhibited potent antigrowth activity both in cancer cell lines and in mouse xenograft models. They are nearly equipotent on HER-2 and EGFR, >50-fold selective for these two receptors versus other proliferative kinases, and ninefold to >75-fold more potent on tumour cells than on normal cells. The most potent and selective compounds were GW2974 and, to a lesser extent, GW0277. Their mechanism of action seems to be related to a 90% reduction in autophosphorylation of both HER-2 and EGFR: short term exposure of HN5 and BT474 xenografts to GW2974 resulted in dramatic inhibition of autophosphorylation - of EGFR and HER-2, respectively - even though levels of overexpression of both receptors remained unchanged. Oral daily treatment of animal models with these compounds resulted in significant inhibition of tumour growth at doses of 10 mg/kg and 30 mg/kg, and tumour regression at higher doses. These compounds, particularly GW2974, were well tolerated.