Molecular Formula | C26H25ClF3N5O3 |
Molar Mass | 547.96 |
Density | 1.39 |
Melting Point | 167-169℃ |
Boling Point | 705.5±60.0 °C(Predicted) |
Solubility | Soluble in DMSO, not in water |
pKa | 14.56±0.29(Predicted) |
Storage Condition | -20℃ |
Use | TAK-285 is a novel dual erbB protein kinase inhibitor that specifically targets human epidermal growth factor receptor (EGFR) and HER2. Methods: TAK-285 is currently being developed by Takeda. TAK-285 was found to be well tolerate in Phase I trials. Absorption of TAK-285 was rapid after oral dosing, and plasma exposure at steady-state increased in a dose-proportional fashion for doses ranging from 50 to 300 mg b.i.d. A partial response was observed for one patient with parotid cancer who received 300 mg b.i.d. The toxicity profile and PK properties of oral TAK-285 warrant further evaluation. |
Target | Aurora B;EGFR/HER1;HER2;HER4;MEK1 |
In vitro study | Of the 34 kinases tested, TAK-285 significantly inhibited HER4 with an IC50 of 260 nM and slightly inhibited MEK1, MEK5, c-Met, Aurora B, Lck, CSK, and SYN B, the IC50 values were 1.1 µm, 5.7 µm, 4.2 µm, 1.7 µm, 2.4 µm, 4.7 µm, and 5.2 µm, respectively, but no effect on other kinases, IC50 >10 μm. TAK-285 acts on BT-474 cells, a human thymic carcinoma cell line that overexpresses HER2, and significantly inhibits growth with a GI50 of 17 nM. The effect of TAK-285 on HER2 and EGFR was similar compared to SYR127063, a potent inhibitor of HER2. The mutant and shortened cut-off patterns used for structural assays HER2-KD and EGFR-KD did not significantly alter TAK-285 inhibitory activity (IC50) compared to the cytoplasmic domain of the wild-type protein. TAK-285 binds to the inactive structure of EGFR and has a similar binding pattern to Lapatinib at the active site. of the 34 kinases tested, TAK-285 significantly inhibited HER4 with an IC50 of 260 nM and slightly inhibited MEK1, MEK5, On c-Met, Aurora B, Lck, CSK, and SYN B had an IC50 of 1.1 µm, 5.7 µm, 4.2 µm, 1.7 µm, 2.4 µm, and 4.7 µm, respectively, and 5.2 μM, but no effect on other kinases, IC50 >10 μm. TAK-285 acts on BT-474 cells, a human thymic carcinoma cell line that overexpresses HER2, and significantly inhibits growth with a GI50 of 17 nM. The effect of TAK-285 on HER2 and EGFR was similar compared to SYR127063, a potent inhibitor of HER2. The mutant and shortened cut-off patterns used for structural assays HER2-KD and EGFR-KD did not significantly alter TAK-285 inhibitory activity (IC50) compared to the cytoplasmic domain of the wild-type protein. TAK-285 binds to the inactive structure of EGFR and has a similar binding pattern to Lapatinib at the active site. |
In vivo study | The oral bioavailability at 50 mg/kg in rats and mice TAK-285 was 97.7% and 72.2%, respectively. TAK-285, the mouse model of BT-474 transplanted tumor with overexpression of HER2 was treated orally at a dose of 100 mg/kg, twice a day for 14 days, which had significant anticancer effect, the T/C ratio was 29%, but did not affect body weight. Similar to the BT-474 model, TAK-285 also inhibited the growth of 4-1St (human gastric cancer tumor overexpressing HER2) xenografts in a dose-dependent manner, treatment at 50 mg/kg and 100 mg/kg twice daily with T/C of 44% and 11%, respectively, did not result in a significant reduction in body weight of the mice. Moreover, TAK-285 treatment inhibited 4-1ST tumor growth in rats in a dose-dependent manner, with T/C of 6.25 and 12.5 at 38% mg/kg and 14% mg/kg, respectively, while at 25 mg/kg and 50 mg/kg mg/kg dose treatment caused tumor regression with T/C of-12% and-16%, respectively. The oral bioavailability of 50 mg/kg in rats and mice TAK-285 was 97.7% and 72.2%, respectively. TAK-285, the mouse model of BT-474 transplanted tumor with overexpression of HER2 was treated orally at a dose of 100 mg/kg, twice a day for 14 days, which had significant anticancer effect, the T/C ratio was 29%, but did not affect body weight. Similar to the BT-474 model, TAK-285 also inhibited the growth of 4-1St (human gastric cancer tumor overexpressing HER2) xenografts in a dose-dependent manner, treatment at 50 mg/kg and 100 mg/kg twice daily with T/C of 44% and 11%, respectively, did not result in a significant reduction in body weight of the mice. Moreover, TAK-285 treatment inhibited 4-1ST tumor growth in rats in a dose-dependent manner, with T/C of 6.25 and 12.5 at 38% mg/kg and 14% mg/kg, respectively, while at 25 mg/kg and 50 mg/kg mg/kg dose treatment caused tumor regression with T/C of-12% and-16%, respectively. |
Reference Show more | 1. Ishikawa T, et al. J Med Chem, 2011, 54(23), 8030-8050.2. Aertgeerts K, et al. J Biol Chem, 2011, 286(21), 18756-18765.3. Erdo F, et al. Brain Res Bull, 2012, 87(4-5), 413-419. |
1mg | 5mg | 10mg | |
---|---|---|---|
1 mM | 1.825 ml | 9.125 ml | 18.25 ml |
5 mM | 0.365 ml | 1.825 ml | 3.65 ml |
10 mM | 0.182 ml | 0.912 ml | 1.825 ml |
5 mM | 0.036 ml | 0.182 ml | 0.365 ml |