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GSK2606414

现货
Catalog No.
A3448
PERK抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,050.00
现货
5mg
¥ 990.00
现货
10mg
¥ 1,300.00
现货
50mg
¥ 3,500.00
现货
200mg
¥ 9,000.00
现货

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Background

GSK2606414 is a selective inhibitor of PERK with IC50 value of 0.4nM.[1]
PERK (PRKR-like endoplasmic reticulum kinase or protein kinase R (PKR)-like endoplasmic reticulum kinase) is also known as EIF2AK3 (Eukaryotic translation initiation factor 2-alpha kinase 3). PERK is encoded by EIF2AK3 gene. It belongs to  type I membrane protein family. It located in the ER (endoplasmic reticulum) and is induced by ER stress which is caused from malfolded proteins. It causes the inactive of EIF2 (eukaryotic translation-initiation factor 2) by phosphorylating the alpha subunit. PERK can lead to repression of global protein synthesis and a rapid reduction of translational initiation. PERK has been identified to interact with NFE2L2 and DNAJC3. PERK mutation is related to WRS (Wolcott-Rallison syndrome) which is a autosomal recessive disorder with multiple epiphyseal dysplasia,infancy-onset diabetes mellitus, osteopenia, mental retardation, and hepatic and renal dysfunction. [2]
GSK2606414 inhibits the activity of PERK with IC50 of 0.4 nM by measuring the cytoplasmic PERK domain phosphorylation. GSK2606414 directly bind to PERK as measured in X-ray structure. GSK2606414 completely inhibit PERK phosphorylation at 30 nM in A549 cells. GSK2606414 has selective inhibition effect on PERK compared to a panel of 294 kinases. There only 20 protein kinases except PERK inhibited >85% by GSK2606414 at 10 μM. GSK2606414 inhibited tumor growth with a dose-dependent manner from 50 to 150 mg/kg in mice bearing pancreatic human BxPC3 tumors.[1]
References:
[1].    Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WH, Heerding DA, Minthorn E, Mencken T et al: Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem, 55(16):7193-7207.
[2].    Shi Y, An J, Liang J, Hayes SE, Sandusky GE, Stramm LE, Yang NN: Characterization of a mutant pancreatic eIF-2alpha kinase, PEK, and co-localization with somatostatin in islet delta cells. J Biol Chem 1999, 274(9):5723-5730.

文献引用

1. Bowen Wang, Mengxue Zhang, et al. "PERK inhibition mitigates restenosis and thrombosis - a potential low-thrombogenic anti-restenotic paradigm." bioRxiv. 2019 March 18.
2. Chen L, Liu L, et al. "Protein kinase RNA-like ER kinase/eukaryotic translation initiation factor 2α pathway attenuates tumor necrosis factor alpha-induced apoptosis in nucleus pulposus cells by activating autophagy." J Cell Physiol. 2018 Dec 4. PMID:30515797
3. Lu Chen, Lei Liu, et al."Endoplasmic Reticulum Stress Facilitates the Survival and Proliferation of Nucleus Pulposus Cells in TNF-a Stimulus by Activating Unfolded Protein Response."DNA and Cell Biology,2018 Apr 1.
4. Hsieh YY, Lo HL, et al. "EZH2 inhibitors transcriptionally upregulate cytotoxic autophagy and cytoprotective unfolded protein response in human colorectal cancer cells." Am J Cancer Res. 2016 Aug 1;6(8):1661-80. PMID:27648357

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt451.44
Cas No.1337531-36-8
FormulaC24H20F3N5O
SynonymsGSK 2606414;GSK-2606414
Solubility≥22.57 mg/mL in DMSO, ≥12.03 mg/mL in EtOH with ultrasonic and warming, <2.19 mg/mL in H2O
Chemical Name1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethyl)phenyl]ethanone
SDFDownload SDF
Canonical SMILESCN1C=C(C2=C1N=CN=C2N)C3=CC4=C(C=C3)N(CC4)C(=O)CC5=CC(=CC=C5)C(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

激酶实验 [1]:

PKR样内质网激酶(PERK)实验

购买GST-PERK胞质结构域。在Sf9昆虫细胞中,从杆状病毒中纯化6-His全长人eIF2α。eIF2α蛋白通过PBS透析进行缓冲液更换,NHS-LC-生物素对其进行化学修饰,eIF2α蛋白再通过50 mM Tris,pH 7.2,250 mM NaCl,5 mM DTT透析进行缓冲液更换。将蛋白分装,置于-80°C中储存。新鲜配制淬火溶液,加入反应液,终浓度分别为4 nM抗eIF2α磷酸化ser51抗体,4 nM Eu-1024标记的抗兔IgG,40 nM streptavidin Surelight APC和15 mM EDTA。反应在384孔聚苯乙烯低容量板中进行,终体积为10 μL。反应液包含10 mM HEPES,5 mM MgCl2,5 μM ATP,1 mM DTT,2 mM CHAPS,40 nM生物素化的6-His-eIF2α和0.4 nM GST-PERK。将分析化合物溶解于DMSO中,使其浓度达1.0 mM,使用DMSO进行11次系列稀释。将各浓度的分析化合物(0.1 μL)转移至分析板中。使终浓度为0.00017 ~ 10 μM。将GST-PERK溶液加到含化合物的分析板中,在室温下,将其预孵育30分钟。加入ATP和eIF2α开启反应。孵育1h后,加入淬火液。在室温下,将384孔板遮盖2小时,再测定信号。使用Viewlux读数仪定量分析信号。APC信号通过APC/Eu计算标准化至铕信号。每个被试物的结果均用IC50值表示。

细胞实验 [1]:

细胞系

A459细胞

制备方法

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

0.003、0.1和0.3 μM;2小时

实验结果

在A459细胞中,GSK2606414抑制ERK自磷酸化,其IC50值少于0.3 μM。

动物实验 [1]:

动物模型

人胰腺癌BxPC3细胞异种移植模型

给药剂量

~ 150 mg/kg;口服给药

实验结果

在小鼠、大鼠以及犬中,GSK2606414具有较高的口服生物利用度和低至中度的血液清除。在携带人胰腺癌BxPC3细胞的小鼠中,GSK2606414呈剂量依赖性地抑制肿瘤生长。

其它注意事项

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]. Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WH, Heerding DA, Minthorn E, Mencken T et al: Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem, 55(16):7193-7207.

生物活性

Description GSK2606414是一种有效的和选择性的蛋白激酶R样内质网激酶(PERK)抑制剂,IC50值为0.4 nM。
靶点 PERK          
IC50 0.4 nM          

质量控制

化学结构

GSK2606414

相关生物数据

GSK2606414

相关生物数据

GSK2606414

相关生物数据

GSK2606414

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GSK2606414