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  • AG-490 (Tyrphostin B42)
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AG-490 (Tyrphostin B42)

An inhibitor of protein tyrosine kinase

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¥337-600
价格
270-480
AG-490 (Tyrphostin B42)的二维码

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  • 货号: ajci11950
  • CAS: 133550-30-8
  • 别名: 酪氨酸磷酸化抑制剂AG490
  • 分子式: C17H14N2O3
  • 分子量: 294.3
  • 纯度: >98%
  • 溶解度: Soluble in DMSO > 10 mM
  • 储存: Store at -20°C
  • 库存: 现货

Background

AG-490 is a tyrosine kinase inhibitor that inhibits EGFR, Stat-3 and JAK2/3.
AG490 inhibits the activation of Stat-3 by selectively blocking JAK2. AG490 is used to selectively inhibit JAK/Stat-3 activation. At a dose of 10 μM, Stat-3 phosphorylation is decreased by >95% and cell viability is maintained. AG490 at a dose of 10 μM results in >95% decrease in pStat-3 in EGF-stimulated A431 cells with no effect on Stat-3 mass[1]. AG-490 is a potent inhibitor of the JAK3/STAT, JAK3/AP-1, and JAK3/MAPK pathways and their cellular consequences. AG-490 abolishes IL-2-inducible [3H]thymidine incorporation in a dose-dependent manner, displaying an IC50 of 25 μM. AG-490 potently inhibits IL-2-mediated proliferation in T cells, results distinct from previous studies that showed this agent induced apoptosis in ALL cells while exerting apparently no effects on the growth of mitogen-stimulated normal T cells[2].
AG490 significantly inhibits the development of type 1 diabetes (T1D) (p?=?0.02, p?=?0.005; at two different time points). Monotherapy of newly diagnosed diabetic NOD mice with AG490 (1 mg/mouse) markedly results in disease remission in treated animals (n=23) in comparision to the absolute inability (0%; 0/10, p=0.003, Log-rank test) of DMSO and sustained eugluycemia is maintained for several months following drug withdrawal[3]. AG490 (1-10 μg) significantly attenuates ?-carrageenan-induced thermal hyperalgesia in a dose-dependent manner. AG490 also reduces mechanical hyperalgesia[4].



AG-490是一种酪氨酸激酶抑制剂,能够抑制EGFR、Stat-3和JAK2/3。


AG490通过选择性阻断JAK2抑制Stat-3的活化。AG490用于选择性抑制JAK/Stat-3的激活。在10μM的剂量下,Stat-3磷酸化下降超过95%,细胞存活率得到维持。10μM的AG490在EGF刺激的A431细胞中导致pStat-3下降超过95%,对Stat-3的质量没有影响[1]。AG-490是JAK3/STAT、JAK3/AP-1和JAK3/MAPK途径及其细胞后果的有效抑制剂。AG-490通过剂量依赖方式完全消除IL-2诱导的[3H]胸腺嘧啶摄取,显示出25μM的IC50。AG-490能够有效抑制T细胞中IL-2介导的增殖,这与先前的研究结果不同,先前的研究结果表明该药物在诱导急性淋巴细胞白血病细胞凋亡的同时,在激动剂刺激的正常T细胞增殖方面似乎没有任何作用[2]。


AG490显著抑制1型糖尿病(T1D)的发展(p = 0.02,p = 0.005;在两个不同的时间点)。AG490的单独治疗新诊断的糖尿病NOD小鼠(1毫克/小鼠)明显导致治疗动物(n=23)的疾病缓解,相比之下DMSO完全无法缓解疾病(0%;0/10,p = 0.003,Log-rank测试),持续的正常血糖状态在停药后数月得以维持[3]。


AG490(1-10μg)能够显著削弱?-卡拉胶引起的热痛觉过敏,呈剂量依赖性。AG490还能够减轻机械性痛觉过敏[4]。


Reference:
[1]. Dowlati A, et al. Combined inhibition of epidermal growth factor receptor and JAK/STAT pathways results in greater growth inhibition in vitro than single agent therapy. Mol Cancer Ther. 2004 Apr;3(4):459-63
[2]. Wang LH, et al. JAK3, STAT, and MAPK signaling pathways as novel molecular targets for the tyrphostin AG-490 regulation ofIL-2-mediated T cell response. J Immunol. 1999 Apr 1;162(7):3897-904.
[3]. Davoodi-Semiromi A, et al. The tyrphostin agent AG490 prevents and reverses type 1 diabetes in NOD mice. PLoS One. 2012;7(5):e36079.
[4]. Cheppudira BP, et al. Anti-hyperalgesic effects of AG490, a Janus kinase inhibitor, in a rat model of inflammatory pain. Biomed Rep. 2015 Sep;3(5):703-706.

Protocol

Cell experiment:

A colorimetric cell proliferation assay is performed using the CellTiter 96 kit. Briefly, A431 cells are plated in 96-well plates (2000 cells/well) and cultured in DMEM/HAM's F-12 supplemented with 10% FCS for 24 h. Cells are incubated in serum-free media for 24 h. EGF (10 ng/mL) is added to all wells. Tyrphostin AG1478 (0.25 mM) and AG490 (10 mM) are added alone or in combination and the culture is incubated for the appropriate time. Medium is aspirated and CellTiter 96 Aqueous One Solution Reagent (20 μL) is added to each well. The plates are incubated at 37°C for up to 1 h and absorbance recorded at 490 nm using a 96-well plate reader. Data are derived from at least three independent experiments (in triplicate) for the both single agents and combination studies. IC50 values for Tyrphostin AG1478 (EGFR inhibitor) and AG490 (JAK/STAT inhibitor) are determined. The growth inhibitory effects of the combination are quantified using the Calucsyn software program[1].

Animal experiment:

Mice[3] Female NOD/LtJ, NOD.Scid, and BALB/c mice are used. One vial of compound containing 5 mg of AG490 is injected into5 mice (1 mg/mouse) via the i.p route. The control groups are receive the same volume of the vehicle under the same regimens and conditions. Rats[4] A total of 28 Male Sprague-Dawley rats (250-300 g) are used. The experiments are performed in rats 48 h after ?-carrageenan injection. A total of 4 groups (n=6) of rats are randomly included in the dose-response study. Group 1 is the vehicle control, which receive 100 μL i.pl. injection of 3.5% DMSO in saline. Groups 2-4 are injected with 3 different doses of AG490 (1, 5 or 10 μg). To study the effects of naloxone on AG490-induced antinociception, an additional group of rats (group 5; n=4) is observed. Group 5 is co-administered with AG490 (10 μg) and Naloxone (10 μg). The drugs are administered i.pl. in a volume of 100 μl. As reported earlier, the in vivo pharmacological effects of AG490 are observed 4 h after treatment. Thus, the behavioral tests are performed before (baseline assessment) and 4 h after treatment. First, the rats are subjected to the thermal hyperalgesia test; 10 min later, the paw pressure test is performed on the same set of rats. All the experiments are performed between 8:00 a.m. and 2:00 p.m. to reduce the confounding influence of diurnal variations, and all the procedures are performed in a blinded fashion.

参考文献:

[1]. Dowlati A, et al. Combined inhibition of epidermal growth factor receptor and JAK/STAT pathways results in greater growth inhibition in vitro than single agent therapy. Mol Cancer Ther. 2004 Apr;3(4):459-63
[2]. Wang LH, et al. JAK3, STAT, and MAPK signaling pathways as novel molecular targets for the tyrphostin AG-490 regulation ofIL-2-mediated T cell response. J Immunol. 1999 Apr 1;162(7):3897-904.
[3]. Davoodi-Semiromi A, et al. The tyrphostin agent AG490 prevents and reverses type 1 diabetes in NOD mice. PLoS One. 2012;7(5):e36079.
[4]. Cheppudira BP, et al. Anti-hyperalgesic effects of AG490, a Janus kinase inhibitor, in a rat model of inflammatory pain. Biomed Rep. 2015 Sep;3(5):703-706.

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