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Dabrafenib (GSK2118436A) 是一种 Raf 抑制剂,抑制 C-Raf 和 B-RafV600E (IC50=5/0.6 nM),具有 ATP 竞争性。Dabrafenib 具有抗肿瘤活性,可用于治疗 B-RafV600E 突变的黑色素瘤。
Dabrafenib (GSK2118436A) 是一种 Raf 抑制剂,抑制 C-Raf 和 B-RafV600E (IC50=5/0.6 nM),具有 ATP 竞争性。Dabrafenib 具有抗肿瘤活性,可用于治疗 B-RafV600E 突变的黑色素瘤。
规格 | 价格 | 库存 | 数量 |
---|---|---|---|
5 mg | ¥ 541 | 现货 | |
10 mg | ¥ 697 | 现货 | |
25 mg | ¥ 995 | 现货 | |
50 mg | ¥ 1,570 | 现货 | |
100 mg | ¥ 2,459 | 现货 | |
200 mg | ¥ 3,690 | 现货 | |
1 mL x 10 mM (in DMSO) | ¥ 616 | 现货 |
产品描述 | Dabrafenib (GSK2118436A) is a Raf inhibitor that inhibits C-Raf and B-RafV600E (IC50=5/0.6 nM) and is ATP-competitive. Dabrafenib exhibits antitumor activity for the treatment of B-RafV600E-mutated melanoma. |
靶点活性 | C-Raf:6.3 nM (cell free), B-Raf:5.2 nM (cell free), B-Raf (V600E):0.7 nM (cell free) |
体外活性 | 方法:195 种肿瘤细胞用 Dabrafenib 处理 72 h,使用 CellTiter-Glo Assay 检测细胞生长。 结果:编码 BRAFV600E 的 20 个细胞系中有 16 个对 Dabrafenib 敏感 (gIC50<200 nM)。其他 5 个突变 BRAF 细胞系中的 3 个对 Dabrafenib 敏感 (gIC50<30nM),包括 WM-115(BRAFV600D) 和 YUMAC(BRAFV600K)。152 个 RAS/RAF 野生型中的133个和所有 18 个突变 RAS 细胞系对 Dabrafenib 不敏感 (gIC50>10µM)。[1] 方法:黑色素瘤细胞株 LCP(BRAFV600R)、WM266 (BRAFV600D) 和 M257 (BRAFWT) 用 Dabrafenib (3-100 nM) 处理 72 h,使用 Western Blot 检测靶点蛋白表达水平。 结果:与具有野生型 BRAF 的对照细胞相比,具有 BRAFV600D/R 突变的细胞系对磷酸化 ERK 表现出更快更强的抑制作用。[2] |
体内活性 | 方法:为检测体内抗肿瘤活性,将 Dabrafenib (3-100 mg/kg,0.5% hydroxypropylmethylcellulose+0.2% Tween 80 in pH 8.0 distilled water) 灌胃给药给携带人结直肠癌肿瘤 Colo 205 (BRAFV600E) 的 CD1 nu/nu 小鼠,每天一次,持续十四天。 结果:Dabrafenib 显示出剂量依赖性的肿瘤生长抑制作用,8 只小鼠中有 4 只在 100 mg/kg 剂量下显示出部分消退。[1] 方法:为检测体内抗肿瘤活性,将 Dabrafenib (0.1-100 mg/kg,0.5% hydroxypropylmethylcellulose+0.2% Tween 80 in pH 8.0 distilled water) 灌胃给药给携带人恶性黑色素瘤 A375P F11 (BRAFV600E) 的 CD1 nu/nu 小鼠,每天一次,持续十四天。 结果:Dabrafenib 可显著减少携带 B-RafV600E 人类黑色素瘤肿瘤的小鼠的肿瘤生长。100 mg/kg 组中,50% 的治疗动物观察到肿瘤完全消退。[3] |
细胞实验 | A375P-F11 assay: A375P cells were plated in 96-well plates by limiting dilution and single cell-derived clones were harvested and tested for sensitivity to B-Raf inhibitors. The F11 clone was selected for future studies and was named A375P-F11. Cellular pSmad Assay to Measure Anti-TGF-β Activity: Activity of compounds was tested in a mechanistic assay in HepG2 cells. Cells were seeded in 12-well plates at a density of 500,000 cells/well and allowed to adhere overnight at 37℃/5% CO2. Media (BME+10% serum) was removed and compound in serum-free media was added to the cells for 45 minutes at 37℃/5% CO2. Cells were stimulated with 1 ng/ml TGF-β for 60 minutes. Cells were lysed in buffer (25 mM Tris-HCl ph: 7.5, 2 mM EDTA, 2 mM EGTA,1% Triton X-100, 0.1 % SDS, 50 mM sodium-β-glycerophosphate, 2 mM sodium orthovanadate, 12.5 mM sodium pyrophosphate, protease and phosphatase inhibitor cocktails) for 30 minutes, scraped, collected, clarified by centrifugation and prepared for western blots in LDS/reducing reagent. Samples were resolved on 4-12% Bis-Tris gels, transferred to PVDF, and probed for total and phospho-Smad2 using antibodies. Gels were imaged using the odyssey blot scanner and quantified. Phospho:total Smad2 ratios were determined and the IC50 was defined as the concentration of compound which decreased the phospho:total ratio by 50% [1]. |
动物实验 | Cells were implanted in nude mice and grown as tumor xenografts. Dosing began when tumors achieved ~150-200mm^3 volume. GSK2118436 was administered by oral gavage at a dose volume of 0.2 mL/20 gram body weight in 0.5% hydroxypropylmethylcellulose and 0.2% Tween-80 in distilled water pH 8.0. Dosing was daily for duration stipulated. Results are reported as mean tumor volume for n=7-8 mice/group. Tumors were measured twice weekly with Vernier calipers, and tumor volume was estimated from two-dimensional measurements using a prolate ellipsoid equation (Tumor volume mm^3 = (length x width^2) x 0.5). Complete tumor regression was defined as a >93% decrease in an individual tumor volume for at least 1 week [1]. |
别名 | GSK2118436A, GSK2118436, 达拉非尼 |
分子量 | 519.56 |
分子式 | C23H20F3N5O2S2 |
CAS No. | 1195765-45-7 |
存储 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. | ||||||||||||||||||||||||||||||||||||||||
溶解度信息 | Ethanol: < 1 mg/mL (insoluble or slightly soluble) 10% DMSO+40% PEG300+5% Tween 80+45% Saline: 2.8 mg/mL (5.39 mM), Please add co-solvents sequentially, clarifying the solution as much as possible before adding the next one. Dissolve by heating and/or sonication if necessary. Working solution is recommended to be prepared and used immediately. DMSO: 55 mg/mL (105.86 mM) | ||||||||||||||||||||||||||||||||||||||||
溶液配制表 | |||||||||||||||||||||||||||||||||||||||||
10% DMSO+40% PEG300+5% Tween 80+45% Saline/DMSO
DMSO
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