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首页> 外文期刊>Anti-Cancer Drug Design >A comparative cell-based high throughput screening strategy for the discovery of selective tyrosine kinase inhibitors with anticancer activity.
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A comparative cell-based high throughput screening strategy for the discovery of selective tyrosine kinase inhibitors with anticancer activity.

机译：一种基于细胞的比较高通量筛选策略，用于发现具有抗癌活性的选择性酪氨酸激酶抑制剂。

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Growth factor receptor tyrosine kinases (RTK) have been implicated in tumor growth, metastasis and angiogenesis, and are thus considered promising targets for therapeutic intervention in malignant diseases. We present a novel drug discovery strategy to find inhibitors of RTKs based on comparative screening of compound libraries employing functional cellular assays. Cell lines 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 cell lines are based on FDC-P1, a murine myeloid progenitor cell line which allows a direct comparison of results obtained in primary screens. In addition, the same cell lines are suitable for compound optimization and for animal studies. Using this strategy we report the identification of promising lead candidates for further drug development which are highly selective, non-cytotoxic and cell permeable with potencies in the low micromolar range.
机译：生长因子受体酪氨酸激酶（RTK）与肿瘤的生长，转移和血管生成有关，因此被认为是治疗恶性疾病的有希望的靶标。我们提出了一种新的药物发现策略，以基于使用功能性细胞测定的化合物库的比较筛选来发现RTK的抑制剂。已经建立了稳定表达HER2和肝细胞生长因子（HGF），血管内皮生长因子（VEGF），胰岛素样生长因子-1（IGF-1）和表皮生长因子（EGF）受体的细胞系。所有细胞系均基于FDC-P1，FDC-P1是鼠类骨髓祖细胞系，可直接比较在初次筛选中获得的结果。此外，相同的细胞系适用于化合物优化和动物研究。使用这种策略，我们报告了对有希望的潜在候选药物的鉴定，这些候选药物可用于进一步的药物开发，这些药物具有高选择性，无细胞毒性和细胞渗透性，且在低微摩尔范围内具有强大的潜能。

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