TAK-632
作者：齊岳
發布時間：2023-08-28
09:02:41
點擊數：
產品名稱：TAK-632
產品描述：
| 產品描述 | TAK-632 is a potent pan-Raf inhibitor. |
| 靶點活性 | PDGFRβ:120 nM, Aurora B:66 nM, FGFR3:280 nM, B-Raf:8.3 nM, C-Raf:1.4 nM |
| 體外活性 | 在攜帶NRAS突變型黑素瘤的SK-MEL-2異種移植小鼠模型中,口服 TAK-632（60 or 120 mg/kg）抑制 MAPK 信號通路,抑制的發展. |
| 體內活性 | 在A375（GI50=66 nM）和HMVII系（和GI50=200 nM）中,TAK-632能夠抑制細胞增殖。其中,在黑色素瘤A375細胞系(BRAFV600E)中,TAK-632抑制MEK（IC50=2 nM）和ERK磷酸化（IC50=16 nM）。在人類黑色素瘤HMVII細胞系(NRASQ61K/BRAFG469V)中,TAK-632抑制pMEK（IC50=49 nM）和pERK（IC50=50 nM）。 |
| 激酶實驗 | 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. |
| 細胞實驗 | 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. (Only for Reference) |
| 化合物與蛋白結合的復合物 |
Crystal structure of human DHODH with TAK-632 |
| 分子量 | 554.52 |
| 分子式 | C27H18F4N4O3S |
| CAS No. | 1228591-30-7 |
存儲
Powder: -20°C for 3 years | In solvent: -80°C for 2 years
溶解度
DMSO: 93 mg/mL (167.7 mM)
Ethanol: 2 mg/mL (3.6 mM)
H2O: <1 mg/mL
( < 1 mg/mL refers to the product slightly soluble or insoluble )
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