AEE788 (NVP-AEE788) is a novel multitargeted human epidermal receptor (HER) 1/2 and vascular endothelial growth factor receptor (VEGFR) 1/2 receptor family tyrosine kinases inhibitor with IC50 of 2, 6, 77, 59 nM for EGFR, ErbB2, KDR, and Flt-1. In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited with IC50s of 11 and 220 nM, respectively. It efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. AEE788 also inhibits VEGF-induced angiogenesis in a murine implant model. It has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters.
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Source | PLoS One (2017). Figure 4. AEE788 |
| Method | Western blot analyses | |
| Cell Lines | TGCT cell lines | |
| Concentrations | 30 nM | |
| Incubation Time | 24 h | |
| Results | Interestingly, treatment with AEE788 also led to a decreased activation of mTOR in some cell lines |
| Cell Experiment | |
|---|---|
| Cell lines | NCI-H596, BT-474, SK-BR-3, 32D/EGFR, T24, MCF-7 and MCF-7/EGFRvII cells |
| Preparation method | Endothelial Cell Proliferation Assay. To test the effects of AEE788 on serum, VEGF, EGF, and basic fibroblast growth factor (bFGF)-induced proliferation of human umbilical vein endothelial cells an endothelial cell proliferation assay, based on BrdUrd incorporation, was used as already. |
| Concentrations | 0~10µM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | mouse xenografts models NCI-H596 and DU145 tumors |
| Formulation | N-methylpyrrolidone and PEG300 1:9 (v/v) |
| Dosages | 7.5, 15, 30, 50mg/kg *3days weekly for 35 days |
| Administration | p.o. |
| Molecular Weight | 440.58 |
| Formula | C27H32N6 |
| CAS Number | 497839-62-0 |
| Solubility (25°C) | DMSO ≥ 65 mg/mL |
| 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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