GSK2606414
mRNA synthesis
In vitro transcription of capped mRNA with modified nucleotides and Poly(A) tail
Tyramide Signal Amplification (TSA)
TSA (Tyramide Signal Amplification), used for signal amplification of ISH, IHC and IC etc.
Phos Binding Reagent Acrylamide
Separation of phosphorylated and non-phosphorylated proteins without phospho-specific antibody
Cell Counting Kit-8 (CCK-8)
A convenient and sensitive way for cell proliferation assay and cytotoxicity assay
SYBR Safe DNA Gel Stain
Safe and sensitive stain for visualization of DNA or RNA in agarose or acrylamide gels.
Inhibitor Cocktails
Protect the integrity of proteins from multiple proteases and phosphatases for different applications.
GSK2606414是一种选择性的PERK抑制剂,IC50值为0.4 nM[1]。
PRKR样内质网激酶或蛋白激酶R(PKR)样内质网激酶(PERK),也被称为真核翻译起始因子2-α激酶3(EIF2AK3),属于I型膜蛋白家族。PERK位于内质网(ER)中,被错误折叠蛋白引起的ER应激所诱导。PERK通过磷酸化真核翻译起始因子2(EIF2)的α亚基,从而使其失活。PERK可导致整体蛋白合成的抑制和翻译起始的迅速减少。PERK可与NFE2L2和DNAJC3相互作用。PERK突变与Wolcott-Rallison综合征(WRS)相关,是一种常染色体隐性遗传病,会出现多发性骨骺发育不良、婴儿期发病型糖尿病、骨质疏松、智力低下以及肝肾功能不全等症状[2]。
通过测定胞质PERK结构域的磷酸化表明,GSK2606414抑制PERK的活性,IC50值为0.4 nM。X射线结构分析表明,GSK2606414与PERK直接结合。在A549细胞中,GSK2606414在30 nM时完全抑制PERK的磷酸化。与其它294个激酶相比,GSK2606414对PERK具有选择性的抑制效应。除了PERK,只有20个蛋白激酶可被10 μM的GSK2606414所抑制(>85%)。
在人胰腺癌BxPC3异种移植小鼠中,GSK2606414(50-150 mg/kg)剂量依赖性地抑制肿瘤生长[1]。
参考文献:
[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.
- 1. Jorge Antonio Elias Godoy Carlos, Keli Lima, et al. "AD80, a multikinase inhibitor, exhibits antineoplastic effects in acute leukemia cellular models targeting the PI3K/STMN1 axis." Invest New Drugs. 2021 Aug;39(4):1139-1149. PMID: 33475938
- 2. Bowen Wang, Mengxue Zhang, et al. "PERK Inhibition Promotes Post-angioplasty Reendothelialization via Modulating SMC Phenotype Changes." J Surg Res 2020 Aug 29;257:294-305. PMID: 32871430
- 3. Yang PM, Hong YH, et al. "Progressive Rotavirus Infection Downregulates Redox-Sensitive Transcription Factor Nrf2 and Nrf2-Driven Transcription Units." Oxid Med Cell Longev. 2020 Apr 4;2020:7289120. PMID: 32322337
- 4. Yang PM, Hong YH, et al. "p38α/S1P/SREBP2 activation by the SAM-competitive EZH2 inhibitor GSK343 limits its anticancer activity but creates a druggable vulnerability in hepatocellular carcinoma." Am J Cancer Res. 2019 Oct 1;9(10):2120-2139. PMID: 31720078
- 5. Fang MY, Markmiller S, et al. "Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD." Neuron. 2019 Jun 18. pii: S0896-6273(19)30524-0. PMID: 31272829
- 6. Bowen Wang, Mengxue Zhang, et al. "PERK inhibition mitigates restenosis and thrombosis - a potential low-thrombogenic anti-restenotic paradigm." bioRxiv. 2019 March 18.
- 7. 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
- 8. 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.
- 9. 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
Physical Appearance | A solid |
Storage | Store at -20°C |
M.Wt | 451.44 |
Cas No. | 1337531-36-8 |
Formula | C24H20F3N5O |
Synonyms | GSK 2606414;GSK-2606414 |
Solubility | ≥22.57 mg/mL in DMSO; insoluble in H2O; ≥12.03 mg/mL in EtOH with gentle warming and ultrasonic |
Chemical Name | 1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethyl)phenyl]ethanone |
SDF | Download SDF |
Canonical SMILES | CN1C=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 | 蓝冰运输或根据您的需求运输。 |
一般建议 | 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。溶液形式一般不宜长期储存,请尽快用完。 |
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. |
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 |
质量控制和MSDS
- 批次: