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GNF 5

现货
Catalog No.
A8604
Bcr-Abl抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 550.00
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10mg
¥ 450.00
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25mg
¥ 700.00
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50mg
¥ 1,200.00
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100mg
¥ 1,900.00
现货

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Background

GNF-5 is an analogue of GNF-2 and a selective non-ATP competitive inhibitor of Bcr-Abl with an IC50 value of 0.1 to >10 µM in various cancer cell lines.

Bcr-Abl is a fusion gene that results from the head-to-tail fusion of the Bcr and Abl genes[1]. Bcr-Abl upregulates production of tyrosine kinase and plays a central role in the pathogenesis of chronic myelogenous leukemia (CML) [1].

GNF-5 has the same chemical structure as its parent molecule (GNF-2) with the exception of N-hydroxyethyl carboxamide at its 4-position and such modification provided GNF-5 a longer half-life from (2.30 hrs)[2]. Similar with GNF-2, GNF-5 allosterically inhibits the proliferation of Bcr-Abl positive cell by binding to the myristate-binding site of Abl and induces cell apoptosis[3]. In steady-state kinetic analyses, GNF-5 was able to inhibit wild type Abl with an IC50 value of 0.22 µM[2]. In addition, GNF-5 also has a similar effectiveness against various imatinib® resistance cell lines: In E255V and T315I mutant Ba/F3 cells, a 12-day incubation of GNF-5 2 was able to inhibit the proliferation of cells with a IC50 value of 0.38 and 5 µM, respectively[2].

In mice injected with wild-type Bcr-Abl and luciferase expressing Ba/F3 cells, continuous injection of GNF-5 for 7 days (50 mg/kg, twice per day) normalized peripheral blood cell counts, as well as spleen size[2]. When treating mice that injected with imatinib® resistance T315I Bcr–Abl-transduced bone marrow, daily injection of GNF-5 (75 mg/ kg, twice per day) significantly extended the survival day of mice from 24 days to 22 days[2].

References:
[1]. Rumpold, H. & Webersinke, G. 2011. Molecular pathogenesis of Philadelphia-positive chronic myeloid leukemia - is it all BCR-ABL? Curr Cancer Drug Targets, 11, 3-19.
[2].  Zhang, J., Adrian, F. J., Jahnke, W., et al. 2010. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature, 463, 501-506.
[3].  Karunakaran, U., Park, S. J., Jun, D. Y., et al. Non-receptor tyrosine kinase inhibitors enhances β-cell survival by suppressing the PKCδ signal transduction pathway in streptozotocin – induced β-cell apoptosis. Cellular Signalling.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt418.37
Cas No.778277-15-9
FormulaC20H17F3N4O3
Solubility≥20.9mg/mL in DMSO
Chemical NameN-(2-hydroxyethyl)-3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzamide
SDFDownload SDF
Canonical SMILESC1=CC(=CC(=C1)C(=O)NCCO)C2=CC(=NC=N2)NC3=CC=C(C=C3)OC(F)(F)F
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

野生型或Bcr-Abl转化的Ba/F3细胞

制备方法

该化合物在DMSO中的溶解度大于10 mM,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

0-3 μM

实验结果

抑制剂GNF-5抑制野生型Abl,IC50值为0.22 mM,20 mM的ATP浓度下,Dasatinib的IC50值为0.12 mM。Dasatinib抑制肉豆蔻酸位点突变体E505K,IC50值为0.02 mM,但该位点不被GNF-5抑制(IC50 > 10 mM)。

动物实验: [2]

动物模型

Abl-lox和SM22cre 的C57BL/6小鼠

给药剂量

动物在OVA滴注前1小时和OVA滴注后5小时用10 mg/kg GNF-5或PBS鼻内滴注,持续三周。

实验结果

在Abl条件敲除小鼠中,卵清蛋白处理的支气管肺泡灌洗液中IL-13和CCL2的水平没有受到影响,但imatinib和GNF-5治疗后,动物中的气道阻力和平滑肌生长受到影响。用imatinib或GNF-5治疗后,抑制OVA致敏和攻击的小鼠中分离的小鼠气管环中ACh诱导的收缩。用imatinib或GNF-5处理减少用OVA处理的BALB/c小鼠中PCNA的荧光强度。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Iacob RE, Zhang J, Gray NS et al. Allosteric interactions between the myristate- and ATP-site of the Abl kinase. PLoS One. 2011 Jan 10;6(1):e15929.

[2]. Cleary RA, Wang R, Wang T et al. Role of Abl in airway hyperresponsiveness and airway remodeling. Respir Res. 2013 Oct 11;14:105.

生物活性

Description GNF-5是Bcr-Abl的选择性变构抑制剂,IC50值为220 nM。
靶点 Bcr-Abl          
IC50 220 nM          

质量控制

化学结构

GNF 5