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Tyrphostin AG 879

现货
Catalog No.
B1544
HER2 抑制剂
组合的产品项目
规格价格库存 数量
5mg
¥ 500.00
现货
10mg
¥ 800.00
现货
25mg
¥ 1,900.00
现货

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Background

Tyrphostin AG879 is a tyrosine kinase inhibitor that inhibits the phosphorylation of TrKA, but not TrKB and TrKC. Tyrphostin AG879 is also a ErbB2 kinase inhibitor, has at least 500-fold higher selectivity to ErbB2 than EGFR (IC50 > 500 μmol/L). The IC50 of tyrphostinAG879 against ErbB2 is 1 μmol/L [1].

In vitro: AG 879 has been widely used as a Tyr kinase inhibitor specific for ErbB2 and FLK-1, a VEGF receptor. The IC50 value for ErbB2 and FLK-1 was approximately 1 μM. AG 879 at 10 nM blocked the specific interaction between the Tyr-kinase ETK and PAK1 (a CDC42/Rac-dependent Ser/Thr kinase) in cell culture. AG 879 (10 nM) showed no inhibitory effects on the purified ETK and PAK1 directly in vitro, suggesting that this drug blocked the ETK-PAK1 pathway by targeting the highly sensitive kinase upstream of ETK. Src was insensitive to AG 879. FAK was inhibited by 100 nM AG 879, but not by 10 nM AG879 [2]. AG 879 inhibited proliferation of human breast cancer cells through an effect involving inhibition of MAP kinase activation. AG 879 markedly inhibited the expression of the RAF-1 gene, which encoded an upstream MAPKKK. Additionally, AG 879 inhibited the expression of HER-2[3]. Treatment with AG879 (20 μM) dramatically decreased proliferation with a variable increase in apoptosis in Cell lines from human leiomyosarcoma (HTB-114, HTB-115, HTB-88), rhabdomyosarcoma (HTB-82, TE-671), prostatic adenocarcinoma (PC-3), acute promyelocytic leukemia (HL-60) and histiocytic lymphoma (U-937) [4].

In vivo: In athymic NOD/SCID mice grafted with HTB-114 or HL-60, administration of AG879 at 2 mg induced a decrease in cancer growth [4]. AG 879 administration (20 mg/kg) kept 50% of mice absolutely free of RAS-induced sarcomas. In the nude mice carrying v-Ha-RAS transformed NIH 3T3 cells, AG 879 dramatically reduced the size of the growing sarcomas [5].

References:
[1].  Levitzki A1,Gazit A. Tyrosine kinase inhibition: an approach to drug development.Science.1995 Mar 24;267(5205):1782-8.
[2].  He H1,Hirokawa Y,Gazit A,Yamashita Y,Mano H,Kawakami Y,Kawakami,Hsieh CY,Kung HJ,Lessene G,Baell J,Levitzki A,Maruta H. The Tyr-kinase inhibitor AG879, that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1 activation and malignant transformation.Cancer Biol Ther.2004 Jan;3(1):96-101. Epub 2004 Jan 29.
[3].  Larsson LI1. Novel actions of tyrphostin AG 879: inhibition of RAF-1 and HER-2 expression combined with strong antitumoral effects on breast cancer cells.Cell Mol Life Sci.2004 Oct;61(19-20):2624-31.
[4].  Rende M1,Pistilli A,Stabile AM,Terenzi A,Cattaneo A,Ugolini G,Sanna P.
Role of nerve growth factor and its receptors in non-nervous cancer growth: efficacy of a tyrosine kinase inhibitor (AG879) and neutralizing antibodies antityrosine kinase receptor A and antinerve growth factor: an in-vitro and in-vivo study. Anticancer Drugs.2006 Sep;17(8):929-41.
[5].  He H1,Hirokawa Y,Manser E,Lim L,Levitzki A,Maruta H. Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation.Cancer J.2001 May-Jun;7(3):191-202.

Chemical Properties

Physical AppearanceA crystalline solid
StorageStore at -20°C
M.Wt316.46
Cas No.148741-30-4
FormulaC18H24N2OS
Solubility≥31.6mg/mL in DMSO
Chemical Name(E)-3-amino-2-[(3,5-ditert-butyl-4-oxocyclohexa-2,5-dien-1-ylidene)methyl]-3-sulfanylprop-2-enenitrile
SDFDownload SDF
Canonical SMILESCC(C)(C)C1=CC(=CC(=C(N)S)C#N)C=C(C1=O)C(C)(C)C
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 [1,2]:

细胞系

MCF-7细胞,MDA-MB-231细胞,SK-BR-3细胞,人平滑肌肉瘤(HTB-114,HTB-115,HTB-88),横纹肌肉瘤(HTB-82,TE-671),前列腺腺癌(PC-3),急性早幼粒细胞白血病(HL-60)和组织细胞淋巴瘤(U-937)

溶解方法

该化合物在DMSO中的溶解度大于10 mM。若获取更高浓度的溶液,可在37℃下孵育10分钟,随后在超声波浴中摇匀。-20℃以下可储存数月。

反应条件

20 μM,24 h

应用

在MCF-7细胞中,AG 879以剂量依赖性方式减少细胞数,0.4 μM作用显著。AG 879对MDA-MB-231细胞和SK-BR-3细胞具有强效作用。用AG 879处理24小时可抑制ERK-1/2的激活。AG 879显著降低细胞数量和有丝分裂。AG 879(5 μM)在治疗6和24小时后显著降低RAF-1 mRNA的水平。AG 879(5 μM)显著降低HER-2 mRNA的水平。在过表达的SK-BR-3细胞中,AG 879(20 μM)降低HER-2 mRNA水平。在人平滑肌肉瘤(HTB-114、HTB-115、HTB-88),横纹肌肉瘤(HTB-82、TE-671)、前列腺腺癌(PC-3)、急性早幼粒细胞白血病(HL-60)和组织细胞淋巴瘤(U-937)中,使用AG879(20 μM)治疗可显著降低细胞增殖,增加细胞凋亡。

动物实验 [2,3]:

动物模型

HTB-114或HL-60接种的无胸腺NOD/SCID小鼠,携带v-Ha-RAS转化的NIH 3T3细胞的裸鼠

给药剂量

皮下注射

应用

在平滑肌肉瘤或早幼粒细胞白血病细胞(HTB-114或HL-60)接种的免疫抑制小鼠中,AG879(2 mg)显著降低肿瘤大小。在携带v-Ha-RAS转化的NIH 3T3细胞的裸鼠中,AG 879(20 mg/kg)治疗保持50%的小鼠绝对不含RAS诱导的肉瘤,并显著降低生长肉瘤的体积。

注意事项

由于实验环境的不同,实际溶解度可能与理论值略有不同,请测试室内所有化合物的溶解度。

References:

[1]. Larsson L I. Novel actions of tyrphostin AG 879: inhibition of RAF-1 and HER-2 expression combined with strong antitumoral effects on breast cancer cells[J]. Cellular and molecular life sciences, 2004, 61(19): 2624-2631.

[2]. Rende M, Pistilli A, Stabile A M, et al. Role of nerve growth factor and its receptors in non-nervous cancer growth: efficacy of a tyrosine kinase inhibitor (AG879) and neutralizing antibodies antityrosine kinase receptor A and antinerve growth factor: an in-vitro and in-vivo study[J]. Anti-cancer drugs, 2006, 17(8): 929-941.

[3]. He H, Hirokawa Y, Manser E, et al. Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation[J]. Cancer journal (Sudbury, Mass.), 2000, 7(3): 191-202.

质量控制

化学结构

Tyrphostin AG 879