GSK2656157

Alias: GSK2656157; GSK 2656157; GSK-2656157
Cat No.:V0060 Purity: ≥98%
GSK2656157 (GSK-2656157) is a novel, potent, ATP-competitive and highly selective inhibitor of PERK (PRKR-like endoplasmic reticulum kinase or protein kinase R (PKR)-like endoplasmic reticulum kinase) enzyme with IC50 of 0.9 nM in cell-free assays, it has 500-fold greater activity against a panel of 300 kinases.
GSK2656157 Chemical Structure CAS No.: 1337532-29-2
Product category: PERK
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

GSK2656157 (GSK-2656157) is a brand-new, powerful, ATP-competitive, and highly selective inhibitor of the PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase) enzyme with an IC50 of 0.9 nM in cell-free assays and 500-fold higher activity against a panel of 300 kinases. Treatment of GSK2656157 results in a decrease in downstream substrates like phospho-eIF2α, ATF4, and CHOP as well as an inhibition of PERK. BxPC3 cells have demonstrated that PERK inhibition has an impact on de novo protein synthesis.

Biological Activity I Assay Protocols (From Reference)
Targets
EIF2AK3 (PERK) (IC50 = 0.9 nM); EIF2AK1 (HRI) (IC50 = 460 nM); BRK (IC50 = 905 nM); EIF2AK2 (PKR) (IC50 = 905 nM); MEKK3 (IC50 = 954 nM); Aurora B (IC50 = 1259 nM); KHS (IC50 = 1764 nM); LCK (IC50 = 2344 nM); MLK2 (IC50 = 15 nM); MEKK3 (IC50 = 2847 nM); ALK5 (IC50 = 3020 nM); MLCK2 (IC50 = 3039 nM); EIF2AK4(GCN2) (IC50 = 3162 nM); c-MER (IC50 = 3431 nM); PI3Kγ (IC50 = 3802 nM); WNK3 (IC50 = 5951 nM); LRRK2 (IC50 = 6918 nM); ROCK1 (IC50 = 7244 nM); MSK1 (IC50 = 8985 nM); NEK1 (IC50 = 9807 nM); AXL (IC50 = 9808 nM); JAK2 (IC50 = 24547 nM)
ln Vitro
Inhibiting PERK activation and lowering the downstream substrates phospho-eIF2a, ATF4, and CHOP with an IC50 in the 10–30 nM range are the effects of pretreating cells with GSK2656157. Before UPR induction, cells exposed to 1 mM GSK2656157 are able to block this impact on protein synthesis from scratch. GSK2656157 decreases the expression of five of the 84 UPR-related genes (DDIT3, HERPUD1, PPP1R15A, C/EBP-beta, and ERN1) by a factor of more than four. With an IC50 range of 6–25 mM, GSK2656157 has no discernible impact on the growth of any of these cells when exogenous UPR inducers are not present. In different biological contexts, GSK2656157 can be used to assess the biologic function of PERK. [1]
ln Vivo
Complete inhibition of phospho-PERK Thr980 is observed through 8 hours after a single 50 mg/kg oral dose of GSK2656157. Treatment of mice with 50 or 150 mg/kg twice daily doses of GSK2656157 results in dose-dependent inhibition of tumor growth in four models, with tumor growth inhibition reaching 54-114% at the 150 mg/kg, twice daily dose. Potential mechanisms for the observed antitumor effect include altered amino acid metabolism, decreased blood vessel density, and vascular perfusion. Multiple human tumor xenografts are treated with GSK2656157 to inhibit tumor growth in mice. [1]
Enzyme Assay
Recombinant GST-PERK (536-1116 amino acids) with 6-His-full-length human eIF2a as a substrate is used to assess the inhibitory potency of GSK2656157. At GSK, 27 kinases and a panel of 300 kinases are used to evaluate kinase selectivity.
Cell Assay
Antiproliferative activity of GSK2656157 against multiple human tumor cell lines as well as primary human microvascular endothelial cells is evaluated in a 3-day proliferation assay using standard culture medium. GSK2656157, which has an IC50 range of 6 to 25 mM, has no discernible impact on the growth of any of these cells when exogenous UPR inducers are not present.
Animal Protocol
00.5% hydroxypropyl methyl cellulose, 0.1% tween-80 in water (pH 6.75); 150 mg/kg; BID; Oral
human tumor xenograft models
References

[1]. Cancer Res . 2013 Mar 15;73(6):1993-2002.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C23H21FN6O
Molecular Weight
416.45
Exact Mass
416.18
Elemental Analysis
C, 66.33; H, 5.08; F, 4.56; N, 20.18; O, 3.84
CAS #
1337532-29-2
Appearance
white to light yellow solid powder
SMILES
CC1=NC(=CC=C1)CC(=O)N2CCC3=C2C=CC(=C3F)C4=CN(C5=NC=NC(=C45)N)C
InChi Key
PRWSIEBRGXYXAJ-UHFFFAOYSA-N
InChi Code
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)
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
Synonyms
GSK2656157; GSK 2656157; GSK-2656157
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~32 mg/mL (~76.8 mM)
Water: <1 mg/mL (slightly soluble or insoluble)
Ethanol: <1 mg/mL
Solubility (In Vivo)
1% CMC Na: 30mg/mL (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.4012 mL 12.0062 mL 24.0125 mL
5 mM 0.4802 mL 2.4012 mL 4.8025 mL
10 mM 0.2401 mL 1.2006 mL 2.4012 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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Calculation results

Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Biological Data
  • GSK2656157

    Cellular effect of GSK2656157 on PERK signaling and protein translation. Cancer Res, 2013, 73(6), 1993-2002.
  • GSK2656157

  • GSK2656157

    Vascular effects of GSK2656157 in tumor xenografts. Cancer Res, 2013, 73(6), 1993-2002.
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