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| 2mg |
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| 5mg |
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| 10mg |
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| 25mg |
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Purity: ≥98%
TAK-441 is a novel, orally bioavailable, potent and selective Hedgehog (Hh) signaling pathwayinhibitor with acceptable solubility and pharmacokinetic properties. Itbinds to Smo and is being developed for the treatment of cancer. Hedgehog (Hh) signaling is a highly conserved intercellular and intracellular communication mechanism that governs organogenesis and is dysregulated in cancers of numerous tissues, including prostate. TAK-441 suppressed transcription factor Gli1 mRNA expression in tumor-associated stromal tissue and inhibited tumor growth (treatment/control ratio, 3%) in a mouse medulloblastoma allograft model owing to the improved PK profile based on increased solubility. TAK-441is currently in clinical trials for the treatment of advanced solid tumors.
| ln Vitro |
TAK-441 (compound 11d) (0.03–1000 nM, 48 h) exhibits good solubility and strong activity in the Gli-luc reporter, with an IC50 value of 4.4 nM[1]. With IC50 values of 0.0457 and 0.113 mg/ml in the tumor and skin, respectively, TAK-441 (0.03–1000 nM, 48 h) inhibits Gli1 mRNA[1]. The androgen withdrawal-induced Shh up-regulation is not affected by TAK-441 (0.5-500 nM, 48-72 h). However, by interfering with paracrine Hh signaling with the tumor stroma, TAK-441 (0.5-500 nM, 48-72 h) causes LNCaP xenografts to progress more slowly, resistant to castration[3].
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| ln Vivo |
In BALB/c-nu/nu mice, TAK-441 (compound 11d) (oral; 10 mg/kg, 100 mg/kg) exhibits a favorable exposure and good oral absorption[1]. Strong anticancer efficacy is exhibited by TAK-441 (oral, 1 and 25 mg /kg, QD for 14 days), which can produce dose-dependent plasma and tumor concentrations by increasing TAK-441's solubility in Ptc1+/-p53-/-mice receiving medulloblastoma allografts[1]. After oral dosing, TAK-441 (iv, 1 mg/kg; po, 10 mg/kg) can produce enough exposure in rats and dogs[1]. In xenografted mice, TAK-441 (oral; 1, 10, and 25 mg/kg) has dose-dependent anticancer efficacy; the IC50 value for the suppression of tumor development is 0.075 mg/ml[1]. Pharmacokinetic parameters of TAK-441 administered orally and via Alzet infusion (100 mg/kg, single dose) in BALB/c-nu/nu mice[1]. Cmax (lg/mL) AUC (lgh/mL) Compd Mouse PK 10mg/kg Mouse PK 100mg/kg Cmax (lg/mL) AUC (lgh/mL) 1 2.65 12.1 3.63 32.3 11d 5.62 28.3 21.5 206
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: NIH3T3/Gli-luc cells Tested Concentrations: 0.03–1000 nM Incubation Duration: 48 h Experimental Results: demonstrated acceptable solubility and potent Hh inhibitory activity. Cell Cytotoxicity Assay[3] Cell Types: LNCaP cells Tested Concentrations: 0.5-500 nM Incubation Duration: 48-72 h Experimental Results: Did not affect up-regulation of Shh of in vitro viability of LNCaP cells under androgen-deprivedconditionsin. Western Blot Analysis[3] Cell Types: LNCaP, C4-2, DU145 and PC3 cells Tested Concentrations: Incubation Duration: Experimental Results: 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. |
| Animal Protocol |
Animal/Disease Models: rats and dogs[1]
Doses: 1 mg/kg, 10 mg/kg Route of Administration: iv, 1 mg/kg; po, 10 mg/kg Experimental Results: 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/Disease Models: BALB/c-nu/nu (nude) mice[1] Doses: 10 mg/kg, 100 mg/kg Route of Administration: oral; 10 mg/kg, 100 mg/kg Experimental Results: Inhibits Gli1 mRNA in the tumor and skin with IC50 values of 0.0457 mg/mL and 0.113 mg/mL, respectively. Animal/Disease Models: Ptc1+/-p53-/- mice[1] Doses: 1 and 25 mg/ kg Route of Administration: po (oral gavage) 1 and 25 mg/kg, QD for 14 days Experimental Results: demonstrated strong antitumor activity and resulted in a dose-dependent PK profile by improving solubility. |
| References |
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| Additional Infomation |
Smoothened Antagonist TAK-441 is an orally bioavailable pyrrolopyridine derivative and Smoothened (Smo) antagonist with potential antineoplastic activity. Smo antagonist TAK-441 selectively binds to and inhibits the activity Smo, which is a cell surface co-receptor for ligands in the Hedgehog (Hh) family. This may result in a suppression of Hh-mediated signaling pathways, thereby inhibiting the growth of tumor cells in which this pathway is aberrantly activated. Smo is a G-protein coupled receptor that lies just downstream of the Hh cell surface receptor Patched-1 in the Hh pathway; in the absence of ligand, Patched-1 (Ptch1) inhibits Smo, and ligand binding to Ptch1 results in increased levels of Smo. The Hh-mediated signaling pathways play an important role in cellular growth and differentiation, and tissue repair; constitutive activation of this pathway is associated with uncontrolled cellular proliferation in a variety of cancers.
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| Molecular Formula |
C28H31N4O6F3
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|---|---|
| Molecular Weight |
576.564
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| Exact Mass |
576.219
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| CAS # |
1186231-83-3
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| Related CAS # |
1186231-83-3
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| PubChem CID |
44187367
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
761.6±60.0 °C at 760 mmHg
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| Flash Point |
414.4±32.9 °C
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| Vapour Pressure |
0.0±2.7 mmHg at 25°C
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| Index of Refraction |
1.606
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| LogP |
2.64
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
41
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| Complexity |
1020
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| Defined Atom Stereocenter Count |
0
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| Synonyms |
TAK441; TAK441; TAK 441
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: >10mM
Water:
Ethanol:
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7344 mL | 8.6721 mL | 17.3442 mL | |
| 5 mM | 0.3469 mL | 1.7344 mL | 3.4688 mL | |
| 10 mM | 0.1734 mL | 0.8672 mL | 1.7344 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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