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GDC-0879

现货
Catalog No.
A5071
B-Raf抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,400.00
现货
5mg
¥ 1,000.00
现货
25mg
¥ 3,000.00
现货
100mg
¥ 8,000.00
现货

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Background

IC50: 0.13 nM against purified B-Raf V600E enzyme; a cellular pERK IC50 of 63 nM in the MALME-3M cell line

GDC-0879 is synthsized as a potent and selective B-Raf inhibitor. The Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase signaling pathway is reported to be involved in cellular responses, which is relevant to tumorigenesis.

In vitro: GDC-0879 is a B-Raf inhibitor against various in vitro and cell-based assays, such as A375 melanoma and Colo205 colorectal carcinoma cell lines, both of which are V600E B-Raf mutant. When screened against a panel of 140 kinases at its efficaciou dose, GDC-0879 showed expected activity only against C-Raf [1].

In vivo: In mice treated by GDC-0879, both cell line-and patient-derived BRAFV600E tumors exhibited stronger and more sustained pharmacodynamic inhibition (>90% for 8 hours) and improved survival compared with mutant KRAS-expressing tumors. Moreover, it was found that the responsiveness of BRAFV600E melanoma cells to GDC-0879 could be dramatically altered by pharmacologic and genetic modulation of phosphatidylinositol 3-kinase pathway activity [2].

Clinical trial: GDC-0879 is still in the preclinical development stage, and no clinical data are available currently.

References:
[1] Wong H, Belvin M, Herter S, Hoeflich KP, Murray LJ, Wong L, Choo EF.  Pharmacodynamics of 2-[4-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridine-4-yl)-1H-pyrazol-1-yl]ethan-1-ol (GDC-0879), a potent and selective B-Raf kinase inhibitor: understanding relationships between systemic concentrations, phosphorylated mitogen-activated protein kinase kinase 1 inhibition, and efficacy. J Pharmacol Exp Ther. 2009 Apr;329(1):360-7.
[2] Hoeflich KP, Herter S, Tien J, Wong L, Berry L, Chan J, O'Brien C, Modrusan Z, Seshagiri S, Lackner M, Stern H, Choo E, Murray L, Friedman LS, Belvin M.  Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res. 2009 Apr 1;69(7):3042-51.

文献引用

1. Sieber J, Wieder N, et al. "GDC-0879, a BRAF(V600E) Inhibitor, Protects Kidney Podocytes from Death." Cell Chem Biol. 2017 Dec 6. PMID:29249695

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt334.37
Cas No.905281-76-7
FormulaC19H18N4O2
Solubility≥16.7mg/mL in DMSO, <2.3 mg/mL in EtOH, <2.62 mg/mL in H2O
Chemical Name2-[4-[(1E)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]ethanol
SDFDownload SDF
Canonical SMILESC1CC(=NO)C2=C1C=C(C=C2)C3=CN(N=C3C4=CC=NC=C4)CCO
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

人黑色素瘤A375细胞

溶解方法

在DMSO中的溶解度大于10 mM。为了获得更高的浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。

反应条件

24 h,10 μM

应用

GDC-0879是一个高效的、具有选择性和口服生物有效性的小分子RAF抑制剂。GDC-0879抑制ERK磷酸化的IC50为63 nmol/L,抑制BRAF突变的Malme3M细胞存活的EC50为0.75 μmol/L。此外,细胞BRAF致癌基因的激活突变和GDC-0879敏感性之间有较强的关联性。

动物实验[2]:

动物模型

肿瘤移植的雌性无胸腺nu/nu裸鼠

剂量

口服给药,15,25,50,100和200 mg/kg

应用

GDC-0879以剂量依赖的方式抑制荷瘤小鼠A375异种移植瘤的生长,并且以浓度依赖的方式抑制A375移植瘤中MEK1的磷酸化,抑制MEK1磷酸化的IC50为3.06 μM。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1]. Hoeflich K P, Herter S, Tien J, et al. Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression[J]. Cancer research, 2009, 69(7): 3042-3051.

[2]. Wong H, Belvin M, Herter S, et al. Pharmacodynamics of 2-{4-[(1E)-1-(hydroxyimino)-2, 3-dihydro-1H-inden-5-yl]-3-(pyridine-4-yl)-1H-pyrazol-1-yl} ethan-1-ol (GDC-0879), a potent and selective B-Raf kinase inhibitor: understanding Relationships between systemic concentrations, phosphorylated mitogen-activated protein kinase kinase 1 inhibition, and efficacy[J]. Journal of Pharmacology and Experimental Therapeutics, 2009, 329(1): 360-367.

生物活性

描述 GDC-0879是一种新型有效的和选择性的B-Raf抑制剂,IC50值为0.13 nM。
靶点 B-Raf c-Raf        
IC50 0.13 nM          

质量控制

化学结构

GDC-0879

相关生物数据

GDC-0879