生物活性 | |||
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靶点 |
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描述 | IGF-1R (insulin-like growth factor-1 receptor) plays a key role in transformation, growth and survival of malignant cells, and has been considered as a general and promising target for cancer treatment. Linsitinib is a potent and selective IGF-1R receptor with IC50 value of 35nM, also show inhibitory effect against Insulin receptor and insulin receptor-related receptor with IC50 values of 75nM for both (measured by purified recombinant kinase activity). Treatment with Linsitinib at concentration ranging in 0.01-1μM for 2h could dose-dependently inhibited autophosphorylation of IGF-1R, at phosphorylation of the downstream, including AKT, ERK and p70S6K with IC50 of 24nM, 130nM, 28nM and 60nM, respectively, in 3T3/huIGF-1R (LISN) cells. Also the inhibition on phosphorylation of both IGF-1R and IR by Linsitinib was shown in HT-29 and Colo-205 cells. The antiproliferative effect of Linsitinib could be observed in a panel of cell lines from various tumor types with IC50 ranging in 0.021-0.81μM, including HT29, Colo205, SW620 (colorectal), DU4475, MCF7 (breast), 3T3/huIGF-1R (mouse fibroblast), H358, H292 (non-small-cell lung), BxPC3 (pancreatic) and A673 (rhabdomyosarcoma) cell lines. A further study showed that a panel of non-small-cell lung cancer and colorectal cancer (CRC) tumor cell lines exhibiting an epithelial phenotype exhibited greater sensitivity to Linsitinib than those tumor cells that have undergone an epithelial–mesenchymal transition. A single oral dose of 75mg/kg Linsitinib inhibited the autophosphorylation of IGF-1R 2-24h after dose in LISN tumor xenograft models, suggesting the pharmacodynamics of this compound. Oral administration of Linsitinib at 75mg/kg once-daily for 12 days significantly inhibit tumor growth in a LISN xenograft model[1]. | ||
作用机制 | Linsitinib can attach to the ATP-binding pocket of tyrosine kinase receptors, causing dual inhibition of both IR and IGF-1R.[1] |
细胞研究 | |||||
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细胞系 | 浓度 | 检测类型 | 检测时间 | 活动说明 | 数据源 |
22RV1 | Growth Inhibition Assay | IC50=5.80019 μM | SANGER | ||
5637 | Growth Inhibition Assay | IC50=13.7759 μM | SANGER | ||
639-V | Growth Inhibition Assay | IC50=27.0245 μM | SANGER |
实验方案 | |||
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1mg | 5mg | 10mg | |
1 mM 5 mM 10 mM |
2.37mL 0.47mL 0.24mL |
11.86mL 2.37mL 1.19mL |
23.73mL 4.75mL 2.37mL |
参考文献 |
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