Foretinib (GSK1363089) is a broad-spectrum tyrosine kinase inhibitor with IC50s of 0.4 nM and 0.9 nM for Met and KDR.

FLT4:2.8 nM (cell free), FLT3:3.6 nM (cell free), KDR:0.86 nM (cell free), MET:0.4 nM (cell free), Tie2:1.1 nM (cell free), RON:3 nM (cell free)

Foretinib (EXEL-2880) 针对HGF受体家族的酪氨酸激酶展现抑制作用，其IC50值对于Met为0.4 nmol/L，对于Ron为3 nmol/L。EXEL-2880同样抑制KDR, Flt-1和Flt-4，IC50值分别为0.9, 6.8和2.8 nmol/L。EXEL-2880是对细胞内Met的强效抑制剂，在PC-3前列腺细胞和小鼠B16F10黑色素瘤细胞中的IC50值分别为23和21 nmol/L [1]。在MKN-45中，1 μM foretinib能够抑制MET的磷酸化和下游信号分子。此外，1 μM foretinib也能抑制FGFR2和下游分子的磷酸化，说明foretinib针对KATO-III中的FGFR2。Foretinib通过抑制MET，在MKN-45中抑制表皮生长因子受体(EGFR)、HER3和FGFR3的磷酸化，并通过抑制FGFR2在KATO-III中抑制EGFR、HER3和MET的磷酸化 [2]。

通过单次口服灌胃给药，100 mg/kg的EXEL-2880可显著抑制B16F10肿瘤Met的磷酸化，效果持续到24小时。EXEL-2880的每日一次口服灌胃给药，呈剂量依赖性减少肿瘤负担，分别在30和100 mg/kg的剂量下减少了31%和62%。EXEL-2880处理后，肺表面肿瘤负担（通过每个肿瘤的总结节数乘以平均结节直径计算）分别在30和100 mg/kg剂量下减少了50%和58% [1]。Foretinib的每日口服给药（30 mg/kg）显著抑制了所有三种肿瘤异种移植物的生长，从给药后仅七天开始，并持续整个实验过程。此外，经过14天Foretinib治疗后，所有标本中的TEN细胞肿瘤异种移植物完全消失[3]。

Kinase inhibition was investigated using one of three assay formats: [33P]phosphoryl transfer, luciferase-coupled chemiluminescence, or AlphaScreen tyrosine kinase technology. Further assay details are provided in Supplementary Section. IC50 values were calculated by nonlinear regression analysis using XLFit [1].

PC-3 and B16F10 cells were seeded in 24-well plates overnight. The cells were then washed and incubated with serum-free medium for 3 h followed by a 1 h incubation with EXEL-2880 before addition of HGF (100 ng/mL) for 10 min. Met phosphorylation status was determined by ELISA analysis (Supplementary Data). For determination of VEGF-stimulated extracellular signal-regulated kinase phosphorylation, human umbilical vein endothelial cells were seeded in 96-well plates and incubated for 24 h and then serum-starved for another 24 h. A serial dilution of EXEL-2880 was added for 1 h before a 5 min stimulation with VEGF (20 ng/mL). Medium was removed, and the cells were fixed with Cytofix and then treated with 0.6% H2O2. Plates were blocked with 10% FBS and incubated with a mouse monoclonal anti-phosphorylated extracellular signal-regulated kinase p44/42 antibody (E10) followed by incubation with goat anti-mouse IgG-horseradish peroxidase and chemiluminescent detection. IC50 values were calculated based on triplicate experiments [1].

B16F10 tumor cells (2 × 10^5) were implanted via i.v. tail vein injection into mice on day 0. EXEL-2880 or vehicle administration was initiated 3 days after implantation for 10 days followed by assessment of lung tumor burden. Lungs were excised, weighed, and zinc-fixed for 24 h, and the number of nodules formed on all lobe surfaces was counted using a Zeiss stereoscope. Lung nodule diameters were morphometrically measured on digitally captured images. Inhibition of tumor burden as measured by lung wet weight was calculated as follows: % tumor growth inhibition = [(compound treated-naive / vehicle-naive) × 100]. The results for each treatment group (n = 10 animals) were averaged, and statistical t test analysis was done comparing each treatment group to the vehicle-treated control [1].