TAK-632

Catalog No.S7291

For research use only.

TAK-632 is a potent pan-Raf inhibitor with IC50 of 8.3 nM and 1.4 nM for B-Raf(wt) and C-Raf in cell-free assays, respectively, showing less or no inhibition against other tested kinases.

TAK-632 Chemical Structure

CAS No. 1228591-30-7

Selleck's TAK-632 has been cited by 23 publications

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Biological Activity

Description TAK-632 is a potent pan-Raf inhibitor with IC50 of 8.3 nM and 1.4 nM for B-Raf(wt) and C-Raf in cell-free assays, respectively, showing less or no inhibition against other tested kinases.
Features Orally bioavailable, pan-raf inhibitor that targets both wild-type and mutant forms.
Targets
C-Raf [1]
(Cell-free assay)
B-Raf [1]
(Cell-free assay)
Aurora B [1]
(Cell-free assay)
PDGFRβ [1]
(Cell-free assay)
FGFR3 [1]
(Cell-free assay)
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1.4 nM 8.3 nM 66 nM 120 nM 280 nM
In vitro

TAK-632 inhibits phosphorylation of MEK and ERK in melanoma A375 cells (BRAFV600E) with IC50 of 12 nM and 16 nM, respectively. In human melanoma HMVII cells (NRASQ61K/BRAFG469V), TAK-632 also shows strong inhibition of pMEK and pERK with IC50 of 49 nM and 50 nM, respectively. Moreover, TAK-632 also exhibits antiproliferative activity in both A375 and HMVII cells with GI50 of 66 nM and 200 nM, respectively. [1] TAK-632 induces RAF dimerization but inhibits the kinase activity of the RAF dimer because of its slow dissociation from RAF. The combination of TAK-632 and TAK-733 exhibits synergistic antiproliferative effects in BRAF- and NRAS-mutated melanoma cells. [2]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human A375 cells MWDGeY5kfGmxbjDhd5NigQ>? M3;rR|IhcA>? NXrqPWlZUW6qaXLpeIlwdiCxZjDCVmFHKFZ4MEDFJI12fGGwdDDpckBpfW2jbjDBN|c2KGOnbHzzJIF{e2W|c3XkJIF{KHCqb4PwbI9zgWyjdHnvckBw\iCPRVugZYZ1\XJiMjDodpMh[nliV3XzeIVzdiCkbH;0eIlv\yCjbnHsfZNqeyxiSVO1NF0yOiCwTR?= NInOV|MzOzlyNkO0Ni=>
human HMVII cells MlrFSpVv[3Srb36gZZN{[Xl? NIrpbY0zKGh? MYDJcohq[mm2aX;uJI9nKE6UQWPROlFsN0KUQV\HOFY6Xi2vdYThcpQhcW5iaIXtZY4hUE2YSVmgZ4VtdHNiYYPz[ZN{\WRiYYOgdIhwe3Cqb4L5cIF1cW:wIH;mJG1GUyCjZoTldkAzKGi{czDifUBY\XO2ZYLuJIJtd3S2aX7nJIFv[Wy7c3nzMEBKSzVyPUS5JI5O M1T6RlI{QTB4M{Sy
human HT-29 cells NILw[XFHfW6ldHnvckBie3OjeR?= NXnBXppiUW6qaXLpeIlwdiCxZjDCVmFHKFZ4MEDFJI12fGGwdDDpckBpfW2jbjDIWE0zQSClZXzsd{Bie3Onc4Pl[EBieyCyaH;zdIhwenmuYYTpc44hd2ZiTVXLMEBKSzVyPUe1JI5O NYnpcYc6OjN7ME[zOFI>
human HMVII cells MVrQdo9tcW[ncnH0bY9vKGG|c3H5 NUPZdGYxPzJiaB?= MlPyRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCKTW\JTUBk\WyuczDhd5Nme3OnZDDhd{Boem:5dHigbY5pcWKrdHnvckBi\nSncjC3NkBpenNiYomgZ4hmdWlvbIXtbY5me2OnbnPlJINmdGxidnnhZoltcXS7IHHzd4F6NCCJSUWwQVAvOiEQvF2= M2i4VlI{QTB4M{Sy
293 cells NXOxXXNrTnWwY4Tpc44h[XO|YYm= MV2yNEBucW6| MYLJcohq[mm2aX;uJI9nKE5vdHXycYlv[WxiR2PUMZRi\2enZDDNSWsyKCi3bnvuc5dvKG:{aXfpckkh\XiycnXzd4VlKGmwIEK5N{Bk\WyuczD1d4lv\yCJU2StSXJMOSiNN{HBLUBieyC|dXLzeJJifGViYX\0[ZIhOjBibXnud{whUUN3ME2zMlch|ryP NYr0SmF5OjN7ME[zOFI>
In vivo TAK-632 shows superior oral bioavailability in both rats and dogs. TAK-632 (3.9–24.1 mg/kg, p.o.) exhibits dose-dependent antitumor efficacy without severe body weight reduction in a melanoma A375 (BRAFV600E) xenograft model and a human melanoma HMVII (NRASQ61K/BRAFG469V) xenograft in rats. [1] In NRAS-mutant melanoma SK-MEL-2 xenograft model, TAK-632 (60 or 120 mg/kg, p.o.) also exhibits potent antitumor efficacy without severe toxicity. [2]

Protocol (from reference)

Kinase Assay:

[1]

  • Kinase Profile Assay:

    Assays for serine/threonine kinases using radio labeled [γ-33P] ATP are performed in 96 well plates. BRAF and c-RAF are expressed as N-terminal FLAG-tagged protein using a baculovirus expression system. The reaction conditions are optimized for each kinase: BRAF (25 ng/well of enzyme, 1 μg/well of GST-MEK1(K96R), 0.1 μCi/well of [γ-32P] ATP, room temperature, 20 min reaction); c-RAF (25 ng/well of enzyme, 1 μg/well of GST-MEK1 (K96R), 0.1 μCi/well of [γ-32P] ATP, room temperature, 20 min reaction). Enzyme reactions are performed in 25 mM HEPES, pH 7.5, 10 mM magnesium acetate, 1 mM dithiothreitol and 0.5 μM ATP containing optimized concentration of enzyme, substrate and radiolabeled ATP as described above in a total volume of 50 μL. Prior to the kinase reaction, compound and enzyme are incubated for 5 min at reaction temperature as described above. The kinase reactions are initiated by adding ATP. After the reaction period as described above, the reactions are terminated by the addition of 10% (final concentration) trichloroacetic acid. The [γ-33P] or [γ-32P]-phosphorylated proteins are filtered in GFC filter plates with a Cell Harvester and then the plates are washed out with 3% phosphoric acid. The plates are dried, followed by the addition of 40 μL of MicroScint0. The radioactivity is counted by a TopCount scintillation counter.

Cell Research:

[1]

  • Cell lines: A375 and HMVII cells
  • Concentrations: ~2 μM
  • Incubation Time: 72 hours
  • Method:

    The cells are proliferated in appropriate medium (vender recommended) supplemented with 10% heat-inactivated fetal bovine serum (FBS) and antibiotics, in tissue culture dishes placed in a humidified incubator maintained at 37°C in an atmosphere of 5% CO2 and 95% air. The anti-proliferative activity of compound is determined by treating cell lines with the compound for 3 days, followed by measurement of viable cell number in the Cell Titer-Glo assay. The cells are seeded in a 96-multiwell plate at 1500 to 4000 cells per well in medium containing FBS and cells allowed to sit down overnight. After 18–20 h, compounds at various concentrations by serial dilution are added to the cells and were cultured for 3 days in chamber. After the treatment culture, cellular proliferation is determined by a Cell Titer-Glo Luminescent Cell Viability Assay. In brief, 100 bL/well of Cell Titer-Glo Substrate solution is added to each well and the cells were cultured for an additional 10 minutes (approximately). The chemi-luminescence value is measured using a Luminescence Counter 1420 ARVO MX Light. Concentration response curves are generated by calculating the decrease in chemi-luminescence values in compound-treated samples relative to the vehicle (DMSO) treated controls.

Animal Research:

[1]

  • Animal Models: Human melanoma A375 (BRAFV600E) xenograft model and human melanoma HMVII (NRASQ61K/BRAFG469V) xenograft model in rats.
  • Dosages: ~24.1 mg/kg
  • Administration: Oral administration

Solubility (25°C)

In vitro

DMSO 100 mg/mL
(180.33 mM)
Ethanol 2 mg/mL
(3.6 mM)
Water Insoluble

In vivo

Add solvents to the product individually and in order
(Data is from Selleck tests instead of citations):
2% DMSO+98% PEG 300
For best results, use promptly after mixing.

5 mg/mL

Chemical Information

Molecular Weight 554.52
Formula

C27H18F4N4O3S

CAS No. 1228591-30-7
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles C1CC1C(=O)NC2=NC3=C(S2)C(=C(C=C3)OC4=CC(=C(C=C4)F)NC(=O)CC5=CC(=CC=C5)C(F)(F)F)C#N

In vivo Formulation Calculator (Clear solution)

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Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

Molarity Calculator

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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