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 |
| 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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| TRX-221
TRX-221 is an EGFR C797S inhibitor. |
| TAS-3351
TAS-3351 is an EGFR C797S inhibitor. |
| Larotinib mesylate hydrate
Larotinib mesylate hydrate is a potent, broad-spectrum, orally active tyrosine kinase inhibitor (TKI) that primarily targets EGFR with an IC50 of 0.6 nM. |
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