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| 5mg |
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Purity: ≥98%
TAK-593 is a novel, orally bioavailable and potent small-molecule receptor of VEGFR and PDGFR with IC50s of 3.2, 0.95, 1.1, 4.3 and 13 nM for VEGFR1, VEGFR2, VEGFR3, PDFGRα and PDFGRβ, respectively. TAK-593 has potential antineoplastic activity. TAK-593 inhibits VEGFR and PDGFR through specific binding, which may stop angiogenesis and the growth of tumor cells.
| Targets |
VEGFR1 (IC50 = 3.2 nM); VEGFR2 (IC50 = 0.95 nM); VEGFR3 (IC50 = 1.1 nM); PDGFRα (IC50 = 4.3 nM); PDGFRβ (IC50 = 13 nM); PDGFRαV561D (IC50 = 1 nM)
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| ln Vitro |
TAK-593 suppresses HUVEC growth with an IC50 of 0.30 nM. It exhibits strong inhibitory action against the PDGFR (PDGFRα, β: IC50=4.3, 13 nM) and VEGFR (VEGFR1-3: IC50=3.2, 0.95, 1.1 nM) families. TAK-593 exhibits IC50 values greater than 100 nM against all kinases, with the exception of Fms (IC50 = 10 nM) and Ret (IC50 = 18 nM) kinases [1]. Human umbilical vein endothelial cells and human coronary artery smooth muscle cells' cellular phosphorylation and proliferation are both potently inhibited by TAK-593 in response to VEGF and PDGF stimulation. Additionally, TAK-593 strongly suppresses the formation of tubes in co-cultured endothelial cells and fibroblasts caused by VEGF[2].
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| ln Vivo |
TAK-593 suppresses HUVEC growth with an IC50 of 0.30 nM. It exhibits strong inhibitory action against the PDGFR (PDGFRα, β: IC50=4.3, 13 nM) and VEGFR (VEGFR1-3: IC50=3.2, 0.95, 1.1 nM) families. TAK-593 exhibits IC50 values greater than 100 nM against all kinases, with the exception of Fms (IC50 = 10 nM) and Ret (IC50 = 18 nM) kinases [1]. Human umbilical vein endothelial cells and human coronary artery smooth muscle cells' cellular phosphorylation and proliferation are both potently inhibited by TAK-593 in response to VEGF and PDGF stimulation. Additionally, TAK-593 strongly suppresses the formation of tubes in co-cultured endothelial cells and fibroblasts caused by VEGF[2].
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| Enzyme Assay |
In 50 mM TrisHCl pH 7.5, 5 mM MnCl2, 5 mM MgCl2, 0.01% Tween-20, and 2 mM DTT, with 10 μM ATP, 0.1 μg/mL biotinylated polyGluTyr (4:1), and 0.1 nM of VEGFR2, enzyme reactions are carried out. Preincubation involves incubating the compound (TAK-593) and enzyme for five minutes at room temperature before catalytic initiation with ATP. The reactions are stopped by adding 25 μL of 100 mM EDTA, 10 μg/mL donor and acceptor streptavidine beads in 62.5 mM HEPES pH 7.4, 250 mM NaCl, and 0.1% BSA. Plates are read by a plate reader after being incubated in the dark for the entire night[1].
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| Cell Assay |
HUVECs are cultured at 37 C for an entire night in an incubator with 5% CO2 after being seeded at a density of 3000 cells/well in a 96-well plate using Human Endothelial-SFM Growth Medium (Invitrogen) supplemented with 3% fetal bovine serum (FBS). After adding the test compounds (TAK-593) at different concentrations and adding 60 ng/mL VEGF, the cells are cultured for an additional five days. The WST-8 formazan assay, which uses the Cell Counting Kit-8, is used to measure cellular proliferation[1].
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| Animal Protocol |
Rats: Diethyl ether is used to induce anesthesia during the intravenous administration of medication to rats. Blood is drawn from the femoral vein in monkeys, and the tail vein in rats, at 5, 10, (only for IV dosing), 15, 30 min, and 1, 2, 3, 4, 6, 8, 12, 24, 32, and 48 hours (only for monkeys) following dosing. After that, the plasma fraction is extracted from the blood by centrifugation. Until analysis, the plasma is maintained frozen at 20°C. Utilizing a fluorescence detector and high-performance liquid chromatography, the concentration of TAK-593 in plasma is ascertained. The wavelengths of the excitation and emission are 346 and 420 nm, respectively.
Mice: Test compounds are given to female BALB/cAJcl mice that have not been fasted at a dose of 10 mg/kg via cassette dosing. Blood samples are taken following oral administration. To extract the plasma fraction, the blood samples are centrifuged. Acetonitrile with an internal standard is used to deproteinize the plasma samples. Following centrifugation, the supernatant is diluted and then centrifuged once more using a mixture of acetonitrile (9:1, v/v) and 0.01 M ammonium formate solution. By using LC/MS/MS, the compound concentrations in the supernatant are determined[1]. |
| References |
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| Additional Infomation |
TAK-593 has been used in trials studying the treatment of Solid Tumors.
VEGFR/PDGFR Tyrosine Kinase Inhibitor TAK-593 is an oral formulation containing a small-molecule receptor tyrosine kinase inhibitor of both vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) with potential antineoplastic activity. TAK-593 selectively binds to and inhibits VEGFR and PDGFR, which may result in the inhibition of angiogenesis and tumor cell proliferation. |
| Molecular Formula |
C23H23N7O3
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|---|---|
| Molecular Weight |
445.4738
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| Exact Mass |
445.186
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| Elemental Analysis |
C, 62.01; H, 5.20; N, 22.01; O, 10.77
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| CAS # |
1005780-62-0
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| Related CAS # |
1005780-62-0
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| PubChem CID |
24767976
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| Appearance |
White solid powder
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| LogP |
3.618
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
33
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| Complexity |
735
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1([H])C([H])([H])C1([H])[H])N([H])C1=C([H])N2C(C([H])=C([H])C(=N2)OC2C([H])=C([H])C(C([H])([H])[H])=C(C=2[H])N([H])C(C2=C([H])C(C([H])([H])[H])=NN2C([H])([H])[H])=O)=N1
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| InChi Key |
DZFZXPPHBWCXPQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H23N7O3/c1-13-4-7-16(11-17(13)24-23(32)18-10-14(2)27-29(18)3)33-21-9-8-20-25-19(12-30(20)28-21)26-22(31)15-5-6-15/h4,7-12,15H,5-6H2,1-3H3,(H,24,32)(H,26,31)
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| Chemical Name |
N-[5-[2-(cyclopropanecarbonylamino)imidazo[1,2-b]pyridazin-6-yl]oxy-2-methylphenyl]-2,5-dimethylpyrazole-3-carboxamide
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| Synonyms |
TAK-593; TAK593; TAK 593
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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: ≥ 48.5 mg/mL (~108.9 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.67 mg/mL (5.99 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 26.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.67 mg/mL (5.99 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 26.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.67 mg/mL (5.99 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2448 mL | 11.2241 mL | 22.4482 mL | |
| 5 mM | 0.4490 mL | 2.2448 mL | 4.4896 mL | |
| 10 mM | 0.2245 mL | 1.1224 mL | 2.2448 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00773929 | Completed | Drug: TAK-593 | Solid Tumors | Millennium Pharmaceuticals, Inc. | January 2009 | Phase 1 |
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