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Dabrafenib Mesylate (GSK-2118436)

现货
Catalog No.
A3347
BRAF(V600E)抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 650.00
现货
10mg
¥ 700.00
现货
50mg
¥ 1,500.00
现货
100mg
¥ 2,400.00
现货

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Background

GSK2118436 is a selective BRAF V600E inhibitor. BRAF encodes a proto-oncogene B-Raf also known as serine/threonine protein kinase B-Raf. It is critical in regulating the MAPK/ERK signaling pathway. BRAF mutations frequently occur in many human cancers. [1, 2] BRAF V600E mutant is constitutively active, allowing MAPK/ERK activation independent of upstream cues. [3]

GSK2118436 binds to Raf family kinases and inhibits their activity. It is highly selective against B-Raf V600E with IC50 of 0.8 nM, compared to wild type B-Raf and c-Raf with IC50s of 3.2 nM and 5.0 nM, respectively. [4]

GSK2118436 treatment shows selective inhibition of MAPK/ERK activation, proliferation, transformation and tumorigenicity. FDA approved GSK2118436 as a single agent treatment for advanced melanoma with BRAF V600E mutation on May 30, 2013.

GSK2118436 can be taken orally.

References:
[1]Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, Ohtsuru A, Saenko VA, Kanematsu T, Yamashita S. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J. Clin. Endocrinol. Metab. 2003; 88 (9): 4393–7.
[2]Tan YH, Liu Y, Eu KW, Ang PW, Li WQ, Salto-Tellez M, Iacopetta B, Soong R. Detection of BRAF V600E mutation by pyrosequencing. Pathology 2008; 40 (3): 295–8.
[3]Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417: 949-954.
[4]Ma XH, Piao SF, Dey S, McAfee Q, Karakousis G, Villanueva J, Hart LS, Levi S, Hu J, Zhang G, Lazova R, Klump V, Pawelek JM, Xu X, Xu W, Schuchter LM, Davies MA, Herlyn M, Winkler J, Koumenis C, Amaravadi RK. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest. 2014; 124(3): 1406-17.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt615.67
Cas No.1195768-06-9
FormulaC24H24F3N5O5S3
SynonymsGSK-2118436 Mesylate;GSK2118436 Mesylate;GSK 2118436 Mesylate;GSK 2118436B,Tafinlar,
Solubility≥30.75 mg/mL in DMSO, ≥2.74 mg/mL in EtOH with ultrasonic and warming, <2.25 mg/mL in H2O
Chemical NameN-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide;methanesulfonic acid
SDFDownload SDF
Canonical SMILESCC(C)(C)C1=NC(=C(S1)C2=NC(=NC=C2)N)C3=C(C(=CC=C3)NS(=O)(=O)C4=C(C=CC=C4F)F)F.CS(=O)(=O)O
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验[1]:

细胞系

M257野生型BRAF、LCP BRAF V600E和WM266 BRAF V600D黑素瘤细胞系。

溶解方法

可溶于DMSO。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月

反应条件

3-100 nM;72 h

实验结果

在携带突变BRAF的黑色素瘤细胞系中,Dabrafenib显著抑制细胞增殖和磷酸化ERK。

动物实验 [2]:

动物模型

异种移植BRAF V600E(A375P)人肿瘤的雌性CD1 nu/nu小鼠。

剂量

30 mg/kg;14 days;每天一次;口服

溶解方法

0.5%羟丙基甲基纤维素,0.2% Tween 80,溶于pH 8.0蒸馏水,每20g体重给药0.2 mL。

实验结果

Dabrafenib是一种口服生物可利用药物,降低pERK并抑制肿瘤生长。Dabrafenib使pERK和Ki67分别降低89%和28%,并将p27增加54%。

注意事项

请测试室内所有化合物的溶解度,实际溶解度可能与理论值略有不同。这是由实验系统错误引起的,这是正常的。

References:

[1]. Gentilcore G, Madonna G, Mozzillo N, et al. Effect of dabrafenib on melanoma cell lines harbouring the BRAF(V600D/R) mutations. BMC Cancer, 2013, 13: 17.

[2]. King AJ, Arnone MR, Bleam MR, et al. Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PLoS One, 2013, 8(7): e67583.

生物活性

Targets Raf          
IC50 3.2/0.8/5.0 nM (B-Raf/B-RafV600E/ c-Raf)          

质量控制

化学结构

Dabrafenib Mesylate (GSK-2118436)

相关生物数据

Dabrafenib
Growth of Colo 205 tumor xenografts was measured in mice during and for a period following oral q.d. x 14 treatment with 0, 3, 10, 30, and 100 mg/kg dabrafenib. Mean tumor volumes are plotted with their standard error mean and 4 partial regressions out of 8 mice were observed at the 100 mg/kg dose after the 14-day treatment period. The 14-day period of dosing is indicated by the shaded gray bar.