TAK-441 是一种高效的hedgehog (Hh)信号抑制剂，具有口服活性，其IC50值为 4.4 nM。TAK-441 具有较强的抗肿瘤活性。
| 生物活性 | TAK-441 is a highly potent and orally activehedgehog(Hh) signalinginhibitor with anIC50value of 4.4 nM. TAK-441 has strong antitumor activity in solid tumors[1][2][3]. |
| IC50& Target | IC50: 4.4 nM (Gli-luc reporter)[1] |
体外研究
(In Vitro) | TAK-441 (compound 11d) (0.03–1000 nM, 48 h) has potent activity in the Gli-luc reporter with an IC50value of 4.4 nM and good solubility[1].
TAK-441 (0.03–1000 nM, 48 h) inhibits Gli1 mRNA with IC50values of 0.0457 and 0.113 mg/ml in the tumor and skin, respectively[1].
TAK-441 (0.5-500 nM, 48-72 h) does not affect androgen withdrawal-induced Shh up-regulation or viability of LNCaP cells[3].
TAK-441 (0.5-500 nM, 48-72 h) leads to delayed castration-resistant progression of LNCaP xenografts by disrupting paracrine Hh signaling with the tumor stroma[3].
Cell Viability Assay[1] | Cell Line: | NIH3T3/Gli-luc cells | | Concentration: | 0.03–1000 nM | | Incubation Time: | 48 h | | Result: | Showed acceptable solubility and potent Hh inhibitory activity. |
Cell Cytotoxicity Assay[3] | Cell Line: | LNCaP cells | | Concentration: | 0.5-500 nM | | Incubation Time: | 48-72 h | | Result: | Did not affect up-regulation of Shh of in vitro viability of LNCaP cells under androgen-deprivedconditionsin. |
Western Blot Analysis[3] | Cell Line: | LNCaP, C4-2, DU145 and PC3 cells | | Concentration: | | | Incubation Time: | | | Result: | Reflected androgen-responsive PCa and express both Shh and Dhh in LNCaP and C4-2 cells and reflect restricted Shh expression of CRPC in DU145 and PC3 cells. |
|
体内研究
(In Vivo) | TAK-441 (compound 11d) (oral; 10 mg/kg, 100 mg/kg) has favorable exposure and good oral absorption in BALB/c-nu/nu mice[1].
TAK-441 (oral, 1 and 25 mg/kg, QD for 14 days) has strong antitumor activity and can achieve dose-dependent plasma and tumor concentrations by improving the solubility of TAK-441 in Ptc1+/-p53-/-mice bearing medulloblastoma allografts[1].
TAK-441 (iv, 1 mg/kg; po, 10 mg/kg) is able to achieve sufficient exposure following oral administration in rats and dogs[1].
TAK-441 (oral; 1, 10, and 25 mg/kg) shows dose-dependent antitumor activity in xenografted mice, the IC50value for the tumor growth inhibition is 0.075 mg/ml[1].
Pharmacokinetic Parameters of TAK-441 in BALB/c-nu/nu mice (oral and Alzet infusion administration; 100 mg/kg; single)[1].
| Compd | | | Mouse PK 10mg/kg | | | | Mouse PK 100mg/kg | | | | Cmax (lg/mL) | | AUC (lgh/mL) | | Cmax (lg/mL) | | AUC (lgh/mL) | | 1 | | 2.65 | | 12.1 | | 3.63 | | 32.3 | | 11d | | 5.62 | | 28.3 | | 21.5 | | 206 | |
| Animal Model: | rats and dogs[1] | | Dosage: | 1 mg/kg, 10 mg/kg | | Administration: | iv, 1 mg/kg; po, 10 mg/kg | | Result: | | Compd | | | Mouse PK 10mg/kg | | | | Vss(mL/kg) | CL (mL/h/kg) | AUC0–24h,iv(ng h/mL) | AUC0–24h,po(ng h/mL) | F (%) | | Rat | 681.6 ± 81.6 | 397.9 ± 10.1 | 2532.3 ± 69.1 | 8031.8 ± 1218.6 | 31.7 | | Dog | 2181.3 ± 82.8 | 161.3 ± 35.6 | 5101.5 ± 685.5 | 45405.6 ± 5812.0 | 90.3 ± 8.8 | |
|
| Animal Model: | BALB/c-nu/nu mice[1] | | Dosage: | 10 mg/kg, 100 mg/kg | | Administration: | oral; 10 mg/kg, 100 mg/kg | | Result: | Inhibits Gli1 mRNA in the tumor and skin with IC50values of 0.0457 mg/mL and 0.113 mg/mL, respectively. |
| Animal Model: | Ptc1+/-p53-/-mice[1] | | Dosage: | 1 and 25 mg/kg | | Administration: | oral, 1 and 25 mg/kg, QD for 14 days | | Result: | Showed strong antitumor activity and resulted in a dose-dependent PK profile by improving solubility. |
|
| Clinical Trial | |
| 分子量 | |
| Formula | |
| CAS 号 | |
| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | Please store the product under the recommended conditions in the Certificate of Analysis. |
