Dovitinib lactate (TKI-258 lactate)(TKI258) lactate is a potent inhibitor of fibroblast growth factor receptor 3 (FGFR3) (IC50 :5 nM).

FGFR3:5 nM

所有细胞对TKI258处理极其敏感，体外半数抑制浓度（IC50）值处于nM范围。与mTOR抑制剂RAD001联合使用时，在这些细胞中观察到细胞死亡和细胞增殖的协同效应[1]。SK-HEP1细胞经dovitinib处理后，观察到G2/M细胞周期阻滞、软琼脂中集落形成的抑制以及bFGF诱导的细胞迁移阻断。Dovitinib抑制了FGFR-1、FRS2-α和ERK1/2的基础表达和FGF诱导的磷酸化[2]。

在体内，dovitinib 强效抑制了六种HCC细胞系的肿瘤生长。与此同时，抑制血管生成与FGFR/PDGFR-β/VEGFR-2信号通路的失活密切相关。dovitinib 还导致视网膜母细胞瘤蛋白去磷酸化，p-histone H2A-X 和 p27 的上调，以及 p-cdk-2 和 cyclin B1 的下调，进而导致细胞增殖减少和肿瘤细胞凋亡的诱导。在一种正位模型中，dovitinib 强效抑制了原发性肿瘤生长和肺转移，并显著延长了小鼠的存活期[2]。

Determination of cell proliferation by 3,[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay.?Different leukemic cells were seeded into a 96-well plate at a density of 5×10^3 cells per well and exposed to different concentrations of TKI258, with or without RAD001, in culture medium.?After incubation for indicated time points.Cell-cycle analysis:For cell-cycle analysis, cells were exposed to different concentrations of TKI258, with or without RAD001, in growth medium.?After different culture durations, cells were harvested and fixed in 70% ethanol at 4°C for over 30 min. After incubation for indicated time points, DNA contents were stained.Apoptosis analysis:Cell apoptosis was detected by determining phosphatidylserine expression on the cell surface[1].

21-0208 and SK-HEP1 cells as well as patient-derived HCC models were employed to study the antitumor effect of dovitinib.?Changes of biomarkers relevant to FGFR/VEGFR/PDGFR pathways were determined by Western blotting.?Microvessel density, apoptosis and cell proliferation were analyzed by immunohistochemistry[1].