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.
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Source | Mol Cancer Ther (2013). Figure 5. E-3810 |
| Method | Immunohistochemistry | |
| Cell Lines | MDA-MB-231 tumor-bearing mice | |
| Concentrations | 20 mg/kg | |
| 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 Experiment | |
|---|---|
| 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 Experiment | |
|---|---|
| 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 |
| Administration | orally |
| Molecular Weight | 443.49 |
| Formula | C26H25N3O4 |
| CAS Number | 1058137-23-7 |
| Solubility (25°C) | DMSO 10 mM |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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