TAK-441
Based on 1 Customer Validation
TAK-441 is a highly potent and orally active hedgehog (Hh) signaling inhibitor with an IC50value of 4.4 nM. TAK-441 has strong antitumor activity in solid tumors.
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- Pureza: 98.47%
- No. CAS: 1186231-83-3
- Fòrmula: C28H31F3N4O6
- Peso molecular:576.56
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Almacenamiento:
-20°C, protect from light
* In solvent : -80°C, 6 months; -20°C, 1 month (protect from light)
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Actividad biológica
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Chemical Information
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Solvente y solubilidad
- Pureza y Documentación
- Referencias
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Help & FAQs
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Actividad biológica
IC50: 4.4 nM (Gli-luc reporter)[1]
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| NIH3T3 | IC50 |
4.4 nM
Compound: 1, TAK-441
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Inhibition of hedgehog signaling pathway in mouse NIH/3T3 cells after 48 hrs by Gli-luciferase reporter gene assay
Inhibition of hedgehog signaling pathway in mouse NIH/3T3 cells after 48 hrs by Gli-luciferase reporter gene assay
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[PMID: 26094943] |
TAK-441 (compound 11d) (0.03–1000 nM, 48 h) has potent activity in the Gli-luc reporter with an IC50 value of 4.4 nM and good solubility[1].
TAK-441 (0.03–1000 nM, 48 h) inhibits Gli1 mRNA with IC50 values 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].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:NIH3T3/Gli-luc cells
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Concentration:0.03–1000 nM
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Incubation Time:48 h
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Result:Showed acceptable solubility and potent Hh inhibitory activity.
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Cell Line:LNCaP cells
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Concentration:0.5-500 nM
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Incubation Time:48-72 h
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Result:Did not affect up-regulation of Shh of in vitro viability of LNCaP cells under androgen-deprivedconditionsin.
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Cell Line:LNCaP, C4-2, DU145 and PC3 cells
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Concentration:
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Incubation Time:
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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.
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 IC50 value 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 | ||||
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:rats and dogs[1]
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Dosage:1 mg/kg, 10 mg/kg
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Administration:iv, 1 mg/kg; po, 10 mg/kg
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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
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Animal Model:BALB/c-nu/nu mice[1]
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Dosage:10 mg/kg, 100 mg/kg
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Administration:oral; 10 mg/kg, 100 mg/kg
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Result:Inhibits Gli1 mRNA in the tumor and skin with IC50 values of 0.0457 mg/mL and 0.113 mg/mL, respectively.
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Animal Model:Ptc1+/-p53-/- mice[1]
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Dosage:1 and 25 mg/kg
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Administration:oral, 1 and 25 mg/kg, QD for 14 days
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Result:Showed strong antitumor activity and resulted in a dose-dependent PK profile by improving solubility.
| NCT Number | Sponsor | Condition | Start Date |
Phase
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|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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No. CAS 1186231-83-3
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Appearance Solid
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Peso molecular 576.56
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Fòrmula C28H31F3N4O6
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Color Off-white to light yellow
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SMILES
O=C(C(N1C)=C(OCC(F)(F)F)C2=C1C=C(CC)N(CC(C3=CC=CC=C3)=O)C2=O)NC4CCN(C(CO)=O)CC4
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
-20°C, protect from light
* In solvent : -80°C, 6 months; -20°C, 1 month (protect from light)
Solvente y solubilidad
DMSO : 100 mg/mL (173.44 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month (protect from light). When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month (protect from light). When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Select the appropriate dissolution method based on your experimental animal and administration route.
- For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
- To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for In Vivo experiments, it is recommended to prepare freshly and use it on the same day.
- The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.
Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% Saline
Solubility: ≥ 2.5 mg/mL (4.34 mM); Clear solution
This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.
Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
Add each solvent one by one: 10% DMSO 90% (20% SBE-β-CD in Saline)
Solubility: 2.5 mg/mL (4.34 mM); Suspended solution; Need ultrasonic
This protocol yields a suspended solution of 2.5 mg/mL. Suspended solution can be used for oral and intraperitoneal injection.
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
Please enter the basic information of animal experiments:
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Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
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%DMSO +
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
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%+
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+%Tween-80 + +
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%Saline +
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Working solution concentration: 0.22 mg/mL
Method for preparing stock solution: mg drug dissolved in μL DMSO. Stock solution concentration: mg/mL. * In solvent : -80°C, 6 months; -20°C, 1 month (protect from light)
1. Take μL DMSO stock solution;
2. Add μL .
μL , mix evenly;
3. Then add μL Tween 80, mix evenly;
4. Then add μL
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Pureza y Documentación
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Ficha de datos (283 KB)
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SDS (252 KB)
- English - EN (252 KB)
- Français - FR (252 KB)
- Deutsch - DE (252 KB)
- Norwegian - NO (252 KB)
- Español - ES (252 KB)
- Swedish - SV (252 KB)
- Italian - IT (252 KB)
- Korean - KR (252 KB)
- Portuguese - PT (252 KB)
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Instrucciones de manejo (2659 KB)
Referencias
[1]. Tomohiro Ohashi, et al. Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: modification of the core skeleton for improved solubility. Bioorg Med Chem. 2012 [Content Brief]
[2]. Akifumi Kogame, et al. Pharmacokinetic and pharmacodynamic modeling of hedgehog inhibitor TAK-441 for the inhibition of Gli1 messenger RNA expression and antitumor efficacy in xenografted tumor model mice. Drug Metab Dispos [Content Brief]
[3]. Naokazu Ibuki, et al. TAK-441, a novel investigational smoothened antagonist, delays castration-resistant progression in prostate cancer by disrupting paracrine hedgehog signaling. Int J Cancer. 2013 Oct 15;133(8):1955-66. [Content Brief]
Complete Stock Solution Preparation Table
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month (protect from light). When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
| Optional Solvent | Concentration Solvent Mass | 1 mg | 5 mg | 10 mg | 25 mg |
|---|---|---|---|---|---|
| DMSO | 1 mM | 1.7344 mL | 8.6721 mL | 17.3442 mL | 43.3606 mL |
| 5 mM | 0.3469 mL | 1.7344 mL | 3.4688 mL | 8.6721 mL | |
| 10 mM | 0.1734 mL | 0.8672 mL | 1.7344 mL | 4.3361 mL | |
| 15 mM | 0.1156 mL | 0.5781 mL | 1.1563 mL | 2.8907 mL | |
| 20 mM | 0.0867 mL | 0.4336 mL | 0.8672 mL | 2.1680 mL | |
| 25 mM | 0.0694 mL | 0.3469 mL | 0.6938 mL | 1.7344 mL | |
| 30 mM | 0.0578 mL | 0.2891 mL | 0.5781 mL | 1.4454 mL | |
| 40 mM | 0.0434 mL | 0.2168 mL | 0.4336 mL | 1.0840 mL | |
| 50 mM | 0.0347 mL | 0.1734 mL | 0.3469 mL | 0.8672 mL | |
| 60 mM | 0.0289 mL | 0.1445 mL | 0.2891 mL | 0.7227 mL | |
| 80 mM | 0.0217 mL | 0.1084 mL | 0.2168 mL | 0.5420 mL | |
| 100 mM | 0.0173 mL | 0.0867 mL | 0.1734 mL | 0.4336 mL |
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