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Besides HER2 and EGFR, TAK-285 only exhibits potent inhibitory activity against HER4 with IC50 of 260 nM. TAK-285 slightly inhibits MEK1, MEK5, c-Met, Aurora B, Lck, CSK, and Lyn B with IC50 of 1.1-5.7 μM. TAK-285 displays potent in vitro antitumor efficacy in HER2-overexpressing BT-474 cells in a dose-dependent manner, and in vivo dose-dependent activity against BT-474 or 4-1ST xenografts in mice and rats. Like SYR127063, TAK-285 binds to the respective kinase in an ATP-competitive manner, which is confirmed by crystallographic data. TAK-285 binds to the inactive conformation of EGFR, and shows a similar binding mode with lapatinib in the active site. The mutations and shortened HER2 and EGFR do not significantly change the inhibitory activity of TAK-285. Given the substantial brain penetration of unbound TAK-285, TAK-285 might have the potential in the treatment of brain metastases of HER2 over-expressing metastatic breast cancer. In Phase I trails, TAK-285 is well tolerated, and rapid absorbed after oral dosing, with the plasma exposure at steady-state increased in a dose-proportional fashion for doses ranging from 50 to 300 mg b.i.d. TAK-285 leads to a partial response in one patient with parotid cancer receiving 300 mg b.i.d.
| Cell Experiment | |
|---|---|
| Cell lines | BT-474 |
| Preparation method | Treating the cells continuously with various concentrations of TAK-285 for 5 days. Counting the live cell numbers with a particle analyzer |
| Concentrations | Dissolved in DMSO, final concentrations ~10 μM |
| Incubation time | 5 days |
| Animal Experiment | |
|---|---|
| Animal models | Female BALB/c nu/nu mice bearing BT-474 or 4-1ST xenografts, and female nude rats (F344/N Jcl-rnu) bearing 4-1ST xenografts |
| Formulation | Suspended in 0.5% (w/v) methylcellulose solution |
| Dosages | ~100 mg/kg/day |
| Administration | Orally twice daily |
| Molecular Weight | 547.96 |
| Formula | C26H25ClF3N5O3 |
| CAS Number | 871026-44-7 |
| Solubility (25°C) | DMSO 100 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
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