Background
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].
参考文献:
[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.
Protocol
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Cell experiment [1]:
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Cell lines
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HT1080 cells
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Preparation method
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The solubility of this compound in DMSO is > 20.8 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reacting condition
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0.1-10 μM, 24 h
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Applications
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In HT1080 cells, 0.1 μM GSK2656157 was efficient to block the activity of PERK. Cells treated with GSK2656157 exhibited increasing eIF2α phosphorylation in order to compensating the loss of PERK.
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Animal experiment [2]:
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Animal models
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Eight- to twelve-week-old naive female CD-1, female nu/nu CD-1 mice and severe combined immunodeficient (SCID) mice
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Dosage form
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50, 150 mg/kg, twice daily
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Application
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After a single 50 mg/kg oral dose of GSK2656157, mice occurs inhibited phospho-PERK in the pancreas completely through 8 hours. And the activity of PERK was recovered to almost normal levels at 18 hours. Twice daily administration of 50 or 150 mg/kg GSK2656157 to mice resulted in an inhibition of multiple tumor xenografts growth in a dose-dependent manner.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1]. Krishnamoorthy J, Rajesh K, Mirzajani F, et al. Evidence for eIF2α phosphorylation-independent effects of GSK2656157, a novel catalytic inhibitor of PERK with clinical implications[J]. Cell Cycle, 2014, 13(5): 801-806.
[2]. Atkins C, Liu Q, Minthorn E, et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity[J]. Cancer research, 2013, 73(6): 1993-2002.
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