GSK2656157

PERK inhibitor CAS# 1337532-29-2

GSK2656157

2D Structure

Catalog No. BCC4983----Order now to get a substantial discount!

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3D structure

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GSK2656157

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Chemical Properties of GSK2656157

Cas No. 1337532-29-2 SDF Download SDF
PubChem ID 53469059 Appearance Powder
Formula C23H21FN6O M.Wt 416.45
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 41 mg/mL (98.45 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2,3-dihydroindol-1-yl]-2-(6-methylpyridin-2-yl)ethanone
SMILES CC1=NC(=CC=C1)CC(=O)N2CCC3=C2C=CC(=C3F)C4=CN(C5=C4C(=NC=N5)N)C
Standard InChIKey PRWSIEBRGXYXAJ-UHFFFAOYSA-N
Standard InChI InChI=1S/C23H21FN6O/c1-13-4-3-5-14(28-13)10-19(31)30-9-8-16-18(30)7-6-15(21(16)24)17-11-29(2)23-20(17)22(25)26-12-27-23/h3-7,11-12H,8-10H2,1-2H3,(H2,25,26,27)
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.
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.
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.

Biological Activity of GSK2656157

DescriptionGSK2656157 is an ATP-competitive and highly selective inhibitor of PERK with an IC50 value of 0.9 nM.
TargetsPERK    
IC500.9 nM     

Protocol

Kinase Assay [1]
BxPC3 (human pancreatic adenocarcinoma) or LL/2 (murine lung carcinoma) cells are treated with DMSO or various concentrations of GSK2656157 for 1 hour, followed by addition of 5 μg/mL tunicamycin or 1 μM thapsigargin for an additional 6 hours to induce endoplasmic reticulum-stress. Cells are lysed in cold radioimmunoprecipitation assay (RIPA) buffer [150 mM NaCl, 50 mM Tris-Cl pH 7.5, 0.25% sodium deoxycholate, 1% NP-40, protease inhibitors, and 100 mM sodium orthovanadate]. Clarified lysates are resolved by SDS-PAGE and transferred to nitrocellulose membrane using NuPAGE system. Blots are incubated with antibodies to total PERK, p-eIF-2α Ser51, total eIF-2α, ATF4, and CHOP. IRDye700DX-labeled goat anti-mouse immunoglobulin G (IgG), IRDye800-CW donkey anti-goat IgG, and IRDye800-CW goat anti-rabbit IgG are used as secondary antibodies. Proteins are detected on the Odyssey Infrared Imager.

Cell Assay [1]
BxPC3 cells are treated with DMSO or 1 μM GSK2656157 for 1 hour before adding 5 μg/mL tunicamycin for an additional hour. Cells are metabolically labeled with 125 μCi 35S-methionine for the subsequent 1 hour. Cells are lysed in cold RIPA buffer and lysates are resolved by SDS-PAGE, followed by exposure to a phosphorimager screen. Control cells are also pretreated with 100 μM cyclohexamide for 1 hour followed by metabolic labeling. Radioisotope incorporation is quantitated using ImageQuant 5.2 software.

Animal Administration [1]
Exponentially growing HPAC (5×106 cells/mouse), Capan-2 (10×106 cells/mouse), or NCI-H929 (1×6 cells/mouse) cells are implanted subcutaneously into the right flank of 8- to 12-week-old female SCID mice. Similarly, 10×106 BxPC3 cells per mouse are implanted in female nude mice. When the tumors reached approximately 200 mm3 in size, the animals are weighed, and block randomized according to tumor size into treatment groups of 8 mice each. Mice are dosed orally with the formulating vehicle or GSK2656157. Mice are weighed and tumors measured by calipers twice weekly. Tumor volumes are calculated. The percentage of tumor growth inhibition is calculated on each day of tumor measurement using the formula: 100× [1 − (average growth of the compound-treated tumors/average growth of vehicle-treated control tumors)].

References:
[1]. Atkins C, et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 2013 Mar 15;73(6):1993-2002. [2]. Krishnamoorthy J, et al. Evidence for eIF2α phosphorylation-independent effects of GSK2656157, a novel catalytic inhibitor of PERK with clinical implications. Cell Cycle. 2014 Mar 1;13(5):801-6. [3]. Ando T, et al. GSK2656157, a PERK inhibitor, reduced LPS-induced IL-1β production through inhibiting Caspase 1 activation in macrophage-like J774.1 cells. Immunopharmacol Immunotoxicol. 2016 Aug;38(4):298-302. [4]. Zhao Q, et al. Thioredoxin-interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhage. J Neuroinflammation. 2017 May 11;14(1):104.

GSK2656157 Dilution Calculator

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GSK2656157 Molarity Calculator

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Preparing Stock Solutions of GSK2656157

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.4012 mL 12.0062 mL 24.0125 mL 48.025 mL 60.0312 mL
5 mM 0.4802 mL 2.4012 mL 4.8025 mL 9.605 mL 12.0062 mL
10 mM 0.2401 mL 1.2006 mL 2.4012 mL 4.8025 mL 6.0031 mL
50 mM 0.048 mL 0.2401 mL 0.4802 mL 0.9605 mL 1.2006 mL
100 mM 0.024 mL 0.1201 mL 0.2401 mL 0.4802 mL 0.6003 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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Background on GSK2656157

GSK2656157 is a highly selective inhibitor of protein kinase R-like ER kinase (PERK) with IC50 value of 0.9nM [1].

GSK2656157 is highly selective for PERK enzyme against a panel of 300 kinases. In the BxPC3 pancreatic tumor cell line, treatment of GSK2656157 causes an inhibition of PERK and decreases in the downstream substrates, including phospho-eIF2α, ATF4 and CHOP. The inhibition of PERK results in effects on de novo protein synthesis as shown in BxPC3 cells [1].

In vivo assay shows that a single 50 mg/kg oral dose of GSK2656157 can completely inhibit the Thr980 phosphorylation of endogenous pancreatic PERK in mice. Furthermore, GSK2656157 causes dose-dependent inhibition of tumor growth in human tumor xenograft models of pancreatic cancer (BxPC3, HPAC and Capan2) and multiple myeloma (NCI-H929). Among these cancers, the Capan2 tumor is most sensitive [1].

References:
[1] Atkins C, Liu Q, Minthorn E, Zhang SY, Figueroa DJ, Moss K, Stanley TB, Sanders B, Goetz A, Gaul N, Choudhry AE, Alsaid H, Jucker BM, Axten JM, Kumar R. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 2013 Mar 15;73(6):1993-2002.

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References on GSK2656157

Evidence for eIF2alpha phosphorylation-independent effects of GSK2656157, a novel catalytic inhibitor of PERK with clinical implications.[Pubmed:24401334]

Cell Cycle. 2014;13(5):801-6.

The endoplasmic reticulum (ER)-resident protein kinase PERK is a major component of the unfolded protein response (UPR), which promotes the adaptation of cells to various forms of stress. PERK phosphorylates the alpha subunit of the translation initiation factor eIF2 at serine 51, a modification that plays a key role in the regulation of mRNA translation in stressed cells. Several studies have demonstrated that the PERK-eIF2alpha phosphorylation pathway maintains insulin biosynthesis and glucose homeostasis, facilitates tumor formation and decreases the efficacy of tumor treatment with chemotherapeutic drugs. Recently, a selective catalytic PERK inhibitor termed GSK2656157 has been developed with anti-tumor properties in mice. Herein, we provide evidence that inhibition of PERK activity by GSK2656157 does not always correlate with inhibition of eIF2alpha phosphorylation. Also, GSK2656157 does not always mimic the biological effects of the genetic inactivation of PERK. Furthermore, cells treated with GSK2656157 increase eIF2alpha phosphorylation as a means to compensate for the loss of PERK. Using human tumor cells impaired in eIF2alpha phosphorylation, we demonstrate that GSK2656157 induces ER stress-mediated death suggesting that the drug acts independent of the inhibition of eIF2alpha phosphorylation. We conclude that GSK2656157 might be a useful compound to dissect pathways that compensate for the loss of PERK and/or identify PERK pathways that are independent of eIF2alpha phosphorylation.

GSK2656157, a PERK inhibitor, reduced LPS-induced IL-1beta production through inhibiting Caspase 1 activation in macrophage-like J774.1 cells.[Pubmed:27251848]

Immunopharmacol Immunotoxicol. 2016 Aug;38(4):298-302.

IL-1beta is one of the inflammatory cytokines and is cleaved from pro-IL-1beta proteolytically by activated Caspase 1. For the activation of Caspase 1, inflammasome was formed by two signals, what is called, priming and triggering signals. In this study, it was found that mouse macrophage J774.1 cells, when treated by single large amount of lipopolysaccharide (LPS), produced a significant amount of IL-1beta. On the other hand, IL-1beta production was not detected when treated by a single, small amount of LPS. Then, focusing on endoplasmic reticulum (ER) stress response among stress responses induced by a large amount of LPS, when GSK2656157, a PERK inhibitor, was used for inhibition of ER stress, GSK2656157 reduced IL-1beta production dose-dependently. Next, when Thapsigargin, an ER stress reagent, was added with LPS, IL-1beta production increased more than by LPS alone. Thus, these results suggested that ER stress was involved in LPS-induced IL-1beta production. When the activation of Caspase 1 was examined by fluorescence activated cell sorter analysis, it was found that GSK2656157 inhibited LPS-induced Caspase 1 activation. Further, it was confirmed that GSK2656157 did not affect LPS-induced TNF-alpha production and activation of NF-kappaB and specifically inhibited the PERK/eIF-2alpha pathway. Therefore, it was found that GSK2656157 specifically inhibited ER stress induced by large amount of LPS and reduced LPS-induced IL-1beta production through inhibition of Caspase 1 activation.

Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development.[Pubmed:24900593]

ACS Med Chem Lett. 2013 Aug 12;4(10):964-8.

We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.

Description

GSK2656157 is a selective and ATP-competitive inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) with an IC50 of 0.9 nM.

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