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Experimental Therapeutics |
Departments of Cancer Biology [D. W. R., R. J. M., K. J. A., B. R. K., R. M. C., D. M. M., T. M. G.], Molecular Biochemistry [E. R. W., B. R. R., W. B. K.], Protein Sciences [P. S. B.], Molecular Sciences [S. H. K.], and Medicinal Chemistry [K. L.], GlaxoSmithKline, Research Triangle Park, North Carolina 27709; Departments of Respiratory Systems [K. A., R. H., R. J. S.], Discovery Chemistry [S. G. C., S. B. G., K. J. S., M. C. C.], Oncology [C. S., M. P., J. S.], Molecular Recognition [A. J.], and Cellular Immunology [P. T.], GlaxoSmithKline, Stevenage, Herts SG1 2NY, United Kingdom; Arrow Therapeutics, Ltd., Carlshalton, Surrey SM5 4DS, United Kingdom [S. G. C., J. S.]; Oxford Glycosciences Abindgdon Science Park, Abingdon, Oxon OX14 3YS, United Kingdom [C. S., M. P.]; Oxford BioMedica, Oxford Science Park, Oxford OX4 4GA, United Kingdom [R. H.]
The type I receptor tyrosine kinases constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression of several types of human malignancies. The best characterized of these proteins are the epidermal growth 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 inhibitors of ErbB-2 and EGFR. The compounds demonstrate potent in vitro inhibition of the ErbB-2 and EGFR kinase domains with IC50s <80 nM. Growth of ErbB-2- and EGFR-expressing tumor cell lines is inhibited at concentrations <0.5 µM. Selectivity for tumor cell growth inhibition versus normal human fibroblast growth inhibition ranges from 10- to >75-fold. Tumor growth in 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 day. In addition, the tested compounds caused a reduction of ErbB-2 and EGFR autophosphorylation in tumor fragments from these xenograft models. These data indicate that these compounds have potential use as therapy in the broad population of cancer patients overexpressing ErbB-2 and/or EGFR.
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