GSK2606414PERK inhibitor,potent and selective CAS# 1337531-36-8 |
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Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
| Cas No. | 1337531-36-8 | SDF | Download SDF |
| PubChem ID | 53469448 | Appearance | Powder |
| Formula | C24H20F3N5O | M.Wt | 451.44 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 31 mg/mL (68.67 mM) H2O : < 0.1 mg/mL (insoluble) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethyl)phenyl]ethanone | ||
| SMILES | CN1C=C(C2=C1N=CN=C2N)C3=CC4=C(C=C3)N(CC4)C(=O)CC5=CC(=CC=C5)C(F)(F)F | ||
| Standard InChIKey | SIXVRXARNAVBTC-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C24H20F3N5O/c1-31-12-18(21-22(28)29-13-30-23(21)31)15-5-6-19-16(11-15)7-8-32(19)20(33)10-14-3-2-4-17(9-14)24(25,26)27/h2-6,9,11-13H,7-8,10H2,1H3,(H2,28,29,30) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | Potent and selective protein kinase R-like ER kinase (PERK) inhibitor (IC50 = 0.4 nM). Exhibits >1000-fold selectivity for PERK over HR1 and PKR. Inhibits thapsigargin-induced PERK phosphorylation in lung carcinoma A549 cells. Attenuates subcutaneous pancreatic human tumor xenograft growth in mice. Orally bioavailable. |
GSK2606414 Dilution Calculator
GSK2606414 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.2151 mL | 11.0757 mL | 22.1513 mL | 44.3027 mL | 55.3783 mL |
| 5 mM | 0.443 mL | 2.2151 mL | 4.4303 mL | 8.8605 mL | 11.0757 mL |
| 10 mM | 0.2215 mL | 1.1076 mL | 2.2151 mL | 4.4303 mL | 5.5378 mL |
| 50 mM | 0.0443 mL | 0.2215 mL | 0.443 mL | 0.8861 mL | 1.1076 mL |
| 100 mM | 0.0222 mL | 0.1108 mL | 0.2215 mL | 0.443 mL | 0.5538 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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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.
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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).[Pubmed:22827572]
J Med Chem. 2012 Aug 23;55(16):7193-207.
Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.
Effects of GSK2606414 on cell proliferation and endoplasmic reticulum stressassociated gene expression in retinal pigment epithelial cells.[Pubmed:28358434]
Mol Med Rep. 2017 May;15(5):3105-3110.
GSK2606414 is a novel, highly selective inhibitor of protein kinase Rlike endoplasmic reticulum kinase (PERK). GSK2606414 and its analogues have recently been demonstrated to delay tumor growth and prevent neurodegeneration. The present study investigated the effects of GSK2606414 on proliferation, apoptosis, and the expression of activating transcription factor 4 (ATF4), CCAAT/enhancerbinding protein homologous protein (CHOP) and vascular endothelial growth factor (VEGF) in human retinal pigment epithelial (RPE) cells under endoplasmic reticulum (ER) stress. ARPE19 human RPE cells were treated with 0.0150 microM GSK2606414, and ER stress was induced by thapsigargin (TG) treatment. Cell proliferation was assessed using the Cell Counting kit8 cell viability assay. Apoptosis was detected by AnnexinV/propidium iodide double staining using flow cytometry. Western blot analysis was used to measure eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation levels. ATF4, CHOP and VEGF mRNA expression levels were assessed using reverse transcriptionquantitative polymerase chain reaction. GSK2606414 treatment inhibited RPE cell proliferation in a dosedependent manner, however it did not induce apoptosis. In addition, GSK2606414 treatment inhibited eIF2alpha phosphorylation and reduced CHOP and VEGF mRNA expression levels in RPE cells under TGinduced ER stress. To the best of our knowledge, the present study is the first to demonstrate that GSK2606414 has a potential antiproliferative effect in RPE cells in vitro. This effect appeared to be achieved via inhibition of the PERK/ATF4/CHOP signaling pathway and suppression of VEGF expression levels.
Uncoupling proteostasis and development in vitro with a small molecule inhibitor of the pancreatic endoplasmic reticulum kinase, PERK.[Pubmed:23148209]
J Biol Chem. 2012 Dec 28;287(53):44338-44.
Loss-of-function mutations in EIF2AK3, encoding the pancreatic endoplasmic reticulum (ER) kinase, PERK, are associated with dysfunction of the endocrine pancreas and diabetes. However, to date it has not been possible to uncouple the long term developmental effects of PERK deficiency from sensitization to physiological levels of ER unfolded protein stress upon interruption of PERK modulation of protein synthesis rates. Here, we report that a selective PERK inhibitor acutely deregulates protein synthesis in freshly isolated islets of Langerhans, across a range of glucose concentrations. Acute loss of the PERK-mediated strand of the unfolded protein response leads to rapid accumulation of misfolded pro-insulin in cultured beta cells and is associated with a kinetic defect in pro-insulin processing. These in vitro observations uncouple the latent role of PERK in beta cell development from the regulation of unfolded protein flux through the ER and attest to the importance of the latter in beta cell proteostasis.
