| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| Other Sizes |
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Purity: ≥98%
| Targets |
c-Raf (IC50 = 1.4 nM); Braf (IC50 = 8.3 nM); Aurora B (IC50 = 66 nM); PDGFRβ (IC50 = 120 nM); PDGFRα (IC50 = 610 nM); FGFR3 (IC50 = 280 nM); TIE2 (IC50 = 740 nM); IKKβ (IC50 = 3700 nM); CDK1 (IC50 = 790 nM); CDK2 (IC50 = 580 nM); p38α (IC50 = 600 nM); GSK3β (IC50 = 500 nM); MEK1 (IC50 = 3700 nM)
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| ln Vitro |
TAK-632 has an IC50 range of 120-790 nM and inhibits PDGFRβ, FGFR3, GSK3β, CDK2, P38α, PDGFRα, TIE2, and CDK1. The IC50 range for CHK1, IKKβ, and MEK1 is between 140 and 1700 nM. TAK-632 inhibits BRAF and CRAF after 1 hour of preincubation in an ATP competitive manner (at low ATP concentrations, BRAF IC50: 15 nM; CRAF: 8.1 nM). At high ATP concentrations, TAK-632 loses its biochemical activity against BRAF and CRAF, respectively, to IC50 values of 58 nM and 62 nM. In HMVII cells, TAK-632 exhibits potent inhibition of pMEK and pERK with IC50 values of 49 nM and 50 nM, respectively[1]. TAK-632 exhibits potent antiproliferative properties in both A375 and SK-MEL-2 cells (GI50 in A375 cells is 40–190 nM and GI50 in SK-MEL-2 cells is 190–250 nM)[2].
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| ln Vivo |
TAK-632 exhibits significantly increased oral absorption (at a dose of 25 mg/kg, AUC, 32.47 μg h/mL; F, 51.7%) and significantly improved solubility (740 μg/mL) in pH 6.8 phosphate buffer. The oral bioavailability of TAK-632 at 10 mg/kg in a dog PK study is also superior (F: 108%). Over a dose range of 1.9-24.1 mg/kg, oral single administration of TAK-632 inhibits pERK in tumors at 8 hours after its administration. Particularly, doses of 9.7-24.1 mg/kg of TAK-632 significantly reduce pERK levels to 11% of the control. Over a dose range of 3.9-24.1 mg/kg, TAK-632 demonstrates dose-dependent antitumor efficacy without significantly reducing body weight. Significant tumor regression is seen at doses of 9.7 mg/kg and 24.1 mg/kg (T/C=2.1% and 12.1%, respectively)[1]. In NRAS-mutant melanoma using a SK-MEL-2 xenograft model, TAK-632 exhibits potent antitumor efficacy when orally administered at 60 mg/kg once daily (T/C=37%, P<0.001) or at 120 mg/kg once daily (T/C=29%, P<0.001) for 21 days without severe toxicity[2].
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| Enzyme Assay |
Recombinant inactive MEK (K97R) is incubated with immunoprecipitated BRAF or CRAF at 30°C for 30 minutes in kinase reaction buffer containing ATP/Mg2+. TAK-632 is administered to RAS/RAF wild-type (A431, CsFb, and HeLa), KRAS-mutant (A549, HCT-116, and MIA PaCa-2), and NRAS-mutant (GAK, HMV-II, and SK-MEL-2) melanoma cells at the indicated concentrations for 2 hours. Western blot analysis is used to examine cell lysates[2].
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| Cell Assay |
The Sulforhodamine B assay or the CellTiter-Glo luminescent cell viability assay are both used to measure the viability of cells in three replicates. PCP software was used to determine the TAK-632 concentrations that resulted in 50% growth inhibition (GI50). Software called CalcuSyn is used to determine the combination index (CI). We carried out proliferation assays in various cell lines containing mutated BRAF, NRAS, or KRAS in order to look into the antiproliferative activity of TAK-632. TAK-632 and TAK-733 are cotreated for 72 hours with HMV-II, SK-MEL-2, or A375 cells. Measurements are made of cell viability. Calculations are made to determine the CI value at EC50. TAK-632 and TAK-733 are cotreated with A375 cells for 72 hours if they are transiently expressing NRASQ61K or ΔN-BRAF. Measurements are made of cell viability. Calculations are made to determine the CI value at EC50[2].
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| Animal Protocol |
Mice: The xenograft-implanted nude mice are employed. TAK-632 or vehicle are administered once daily for 21 straight days to mice with SK-MEL-2 xenografts (10 mice in each treatment group). Day 0 marks the start of the course of treatment. Two times a week, tumors are measured. Treatment options include vehicle, TAK-632 at 60 mg/kg (60 mpk), or TAK-632 at 120 mg/kg (120 mpk) once daily (QD) for three days in mice bearing SK-MEL-2 xenografts. After the final treatment, tumor xenografts are collected at the appropriate times and subjected to Western blot analysis. A single electrophoresis gel is used to combine various blots with dividing lines. The bars show the densitometric analysis of phospho-ERK normalized to the vehicle-treated control (mean±SD).
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| References |
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| Additional Infomation |
TAK-632 is a member of the class of benzothiazoles that is 1,3-benzothiazole substituted by (cyclopropanecarbonyl)amino, 4-fluoro-3-{2-[3-(trifluoromethyl)phenyl]acetamido}phenoxy, and cyano groups at positions 2, 6 and 7, respectively. It is a potent pan-RAF inhibitor with IC50 of 1.4, 2.4 and 8.3 nM for CRAF, BRAF(V600E), BRAF(WT), respectively. It has a role as a necroptosis inhibitor, a B-Raf inhibitor, an EC 2.7.11.26 (tau-protein kinase) inhibitor, an antineoplastic agent and an apoptosis inducer. It is a member of monofluorobenzenes, a member of benzothiazoles, an aromatic ether, a secondary carboxamide, a member of (trifluoromethyl)benzenes, a nitrile and a cyclopropylcarboxamide.
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| Molecular Formula |
C27H18F4N4O3S
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|---|---|---|
| Molecular Weight |
554.52
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| Exact Mass |
554.103
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| Elemental Analysis |
C, 58.48; H, 3.27; F, 13.70; N, 10.10; O, 8.66; S, 5.78
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| CAS # |
1228591-30-7
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| Related CAS # |
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| PubChem CID |
46209401
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| Appearance |
White solid powder
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.660
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| LogP |
5.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
39
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| Complexity |
957
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(NC1=CC(OC2=CC=C3N=C(NC(C4CC4)=O)SC3=C2C#N)=CC=C1F)CC5=CC=CC(C(F)(F)F)=C5
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| InChi Key |
OJFKUJDRGJSAQB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H18F4N4O3S/c28-19-7-6-17(12-21(19)33-23(36)11-14-2-1-3-16(10-14)27(29,30)31)38-22-9-8-20-24(18(22)13-32)39-26(34-20)35-25(37)15-4-5-15/h1-3,6-10,12,15H,4-5,11H2,(H,33,36)(H,34,35,37)
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| Chemical Name |
N-[7-cyano-6-[4-fluoro-3-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.51 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), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: ≥ 2.5 mg/mL (4.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 2% DMSO+98% PEG 300: 5mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8034 mL | 9.0168 mL | 18.0336 mL | |
| 5 mM | 0.3607 mL | 1.8034 mL | 3.6067 mL | |
| 10 mM | 0.1803 mL | 0.9017 mL | 1.8034 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.
Effect of TAK-632 on MAPK pathway.Cancer Res.2013 Dec 1;73(23):7043-55. |
Formation of RAF dimer mediates RAF paradoxical activation by TAK-632. A and B, SK-MEL-2 and A549 cells were treated with TAK-632 and vemurafenib at the indicated concentrations for 2 hours, respectively.Cancer Res.2013 Dec 1;73(23):7043-55. |
TAK-632 suppresses the kinase activity of RAF dimer. A, SK-MEL-2 cells were treated with TAK-632 or vemurafenib (vem) at indicated concentrations for 2 hours.Cancer Res.2013 Dec 1;73(23):7043-55. |
Effect of TAK-632 on xenograft proliferation. A, mice bearing SK-MEL-2 xenografts were treated once daily for 21 consecutive days with vehicle or TAK-632 SD at the indicated concentrations (10 mice per each treatment group).Cancer Res.2013 Dec 1;73(23):7043-55. |
TAK-632 suppresses MAPK pathway in vemurafenib-resistant melanoma cells.Cancer Res.2013 Dec 1;73(23):7043-55. |
TAK-632 shows synergy with a MEK inhibitor.Cancer Res.2013 Dec 1;73(23):7043-55. |
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