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.
|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 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|
|Administration||Orally twice daily|
|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.
|Solubility||DMSO 100 mg/mL|
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