The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: Potential therapy for cancer

The type I receptor tyrosine kinases constitute a family of transmembrane p roteins involved in various aspects of cell growth and survival and have be en implicated in the initiation and progression of several types of human m alignancies. The best characterized of these proteins are the epidermal gro wth factor receptor (EGFR) and ErbB-2 (HER-2/neu). We have developed potent quinazoline and pyrido-[3,4-d]-pyrimidine small molecules that are dual in hibitors of ErbB-2 and EGFR. The compounds demonstrate potent in vitro inhi bition of the ErbB-2 and EGFR kinase domains with IC(50)s <80 rnM. Growth o f ErbB-2- and EGFR-expressing tumor cell lines is inhibited at concentratio ns <0.5 muM. Selectivity for tumor cell growth inhibition versus normal hum an fibroblast growth inhibition ranges from 10- to >75-fold. Tumor growth i n mouse s.c. xenograft models of the BT474 and HN5 cell lines is inhibited in a dose-responsive manner using oral doses of 10 and 30 mg/kg twice per d ay. In addition, the tested compounds caused a reduction of ErbB-2 and EGFR autophospborylation in tumor fragments from these xenograft models. These data indicate that these compounds have potential use as therapy in the bro ad population of cancer patients overexpressing ErbB-2 and/or EGFR.