A comparative cell-based high throughput screening strategy for the discovery of selective tyrosine kinase inhibitors with anticancer activity

Growth factor receptor tyrosine kinases (RTK) have been implicated in tumor growth, metastasis and angiogenesis, and are thus considered promising tar gets for therapeutic intervention in malignant diseases, We present a novel drug discovery strategy to find inhibitors of RTKs based on comparative sc reening of compound libraries employing functional cellular assays, Cell li nes stably expressing HER2 and the receptors for hepatocyte growth factor ( HGF), vascular endothelial growth factor (VEGF), insulin-like growth factor -I (IGF-I) and epidermal growth factor (EGF) have been established. All cel l lines are based on FDC-P1, a murine myeloid progenitor cell line which al lows a direct comparison of results obtained in primary screens, In additio n, the same cell lines are suitable for compound optimization and for anima l studies. Using this strategy we report the identification of promising le ad candidates for further drug development which are highly selective, non- cytotoxic and cell permeable with potencies in the low micromolar range.