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受注：045-509-1970 |
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化学情報
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Synonyms | N/A | Storage (From the date of receipt) |
3 years -20°C powder 1 years -80°C in solvent |
| 化学式 | C27H18F4N4O3S |
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| 分子量 | 554.52 | CAS No. | 1228591-30-7 | |
| Solubility (25°C)* | 体外 | DMSO | 100 mg/mL (180.33 mM) | |
| Ethanol | 2 mg/mL (3.6 mM) | |||
| Water | Insoluble | |||
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* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. |
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溶剤液（一定の濃度）を調合する
生物活性
| 製品説明 | 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. |
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| 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] |
| 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] |
| 特徴 | Orally bioavailable, pan-raf inhibitor that targets both wild-type and mutant forms. |
プロトコル(参考用のみ)
| キナーゼアッセイ | Kinase Profile Assay | |
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| 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. | ||
| 細胞アッセイ | 細胞株 | A375 and HMVII cells |
| 濃度 | ~2 μM | |
| 反応時間 | 72 hours | |
| 実験の流れ | 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. |
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| 動物実験 | 動物モデル | Human melanoma A375 (BRAFV600E) xenograft model and human melanoma HMVII (NRASQ61K/BRAFG469V) xenograft model in rats. |
| 投薬量 | ~24.1 mg/kg | |
| 投与方法 | Oral administration | |
参考
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カスタマーフィードバック
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Data from [Data independently produced by , , Oncotarget, 2016, 7(7):8172-83]
Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：
| HDAC Inhibition Restores Response to HER2-Targeted Therapy in Breast Cancer via PHLDA1 Induction [ Int J Mol Sci, 2023, 24(7)6228] | PubMed: 37047202 |
| A Combination of Conformation-Specific RAF Inhibitors Overcome Drug Resistance Brought about by RAF Overexpression [ Biomolecules, 2023, 13(8)1212] | PubMed: 37627277 |
| BRAFΔβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability [ Sci Adv, 2023, 9(35):eade7486] | PubMed: 37656784 |
| Systematic analysis of the MAPK signaling network reveals MAP3K-driven control of cell fate [ Cell Syst, 2022, 13(11):885-894.e4] | PubMed: 36356576 |
| Strategies to inhibit FGFR4 V550L-driven rhabdomyosarcoma [ Br J Cancer, 2022, 10.1038/s41416-022-01973-6] | PubMed: 36097178 |
| A Systems Biology Approach to Investigate Kinase Signal Transduction Networks That Are Involved in Triple Negative Breast Cancer Resistance to Cisplatin [ J Pers Med, 2022, 12-81277] | PubMed: 36013226 |
| Proteasomal down-regulation of the proapoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma [ Life Sci Alliance, 2022, 5(10)e202201445] | PubMed: 36038253 |
| A systematic analysis of signaling reactivation and drug resistance [ Cell Rep, 2021, 35(8):109157] | PubMed: 34038718 |
| Inhibitors of BRAF dimers using an allosteric site [ Nat Commun, 2020, 11(1):4370] | PubMed: 32873792 |
| RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling. [ Nat Med, 2019, 25(2):284-291] | PubMed: 30559419 |
長期の保管のために-20°Cの下で製品を保ってください。
人間や獣医の診断であるか治療的な使用のためにでない。
各々の製品のための特定の保管と取扱い情報は、製品データシートの上で示されます。大部分のSelleck製品は、推薦された状況の下で安定です。製品は、推薦された保管温度と異なる温度で、時々出荷されます。長期の保管のために必要とされてそれと異なる温度で、多くの製品は、短期もので安定です。品質を維持するが、夜通しの積荷のために最も経済的な貯蔵状況を用いてあなたの送料を保存する状況の下に、製品が出荷されることを、我々は確実とします。製品の受領と同時に、製品データシートの上で貯蔵推薦に従ってください。