E-3810 is a novel dual inhibitor of the VEGF and FGF receptors. E-3810 has shown strong antiangiogenic properties as well as outstanding antitumor activity in a large number of preclinical models after oral administration, including resistant settings, and has shown high synergy in combination. E-3810 potently and selectively inhibited VEGF receptor (VEGFR)-1, -2, and -3 and FGF receptor (FGFR)-1 and -2 kinases in the nanomolar range. E-3810 exhibited striking antitumor properties at well-tolerated oral doses administered daily in a variety of tumor xenograft models, including early- or late-stage subcutaneous and orthotopic models. In Matrigel plug assays performed in nude mice, E-3810 inhibited basic FGF-induced angiogenesis and reduced blood vessel density as assessed by histologic analysis. E-3810 reduced the distribution of angiogenesis-sensitive contrast agents after only 5 days of treatment.
|Source||Mol Cancer Ther (2013). Figure 5. E-3810|
|Cell Lines||MDA-MB-231 tumor-bearing mice|
|Incubation Time||1, 4, and 24 hours|
|Results||However, the proportion of necrosis was 2 to 20 times higher than in controls in all groups that received active treatments, except for paclitaxel singleagent, with the largest increase in the groups treated with E-3810 alone or in combination|
|Cell lines||H146 cells|
|Preparation method||Proliferation assay
H146 (2 ~3*103 cells/50 uL/well) in SFM containing 0.5% BSA were cultured in 96-well multi-plates. After overnight culture at 37 C, SFM (150 uL/well) containing 0.5% FBS and several concentrations of SCF were added with or without several concentrations of compound. After culture for 72 hr, the ratios of surviving cells were measured by WST-1.
|Concentrations||0~10 μ M|
|Incubation time||72 h|
|Animal models||Female BALB/c nude mice bearing H146 tumorxenograft model|
|Formulation||0.5% methylcellulose and saline|
|Dosages||30 and 100 mg/kg twice a day from day 1 to day 21|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models.
Bello E, et al. Cancer Res. 2011 Feb 15;71(4):1396-405. PMID: 21212416.
E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition.
Matsui J, et al. Int J Cancer. 2008 Feb 1;122(3):664-71. PMID: 17943726.
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