GSK2656157

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WARNING: This product is for research use only, not for human or veterinary use.

Description:GSK2656157 is an ATP-competitive inhibitor of PERK enzyme activity with an IC50 of 0.9 nM. It is highly selective for PERK with IC50 values >100 nM against a panel of 300 kinases. GSK2656157 inhibits PERK activity in cells with an IC50 in the range of 10-30 nM as shown by inhibition of stress-induced PERK autophosphorylation, eIF2α substrate phosphorylation, together with corresponding decreases in ATF4 and CHOP proteins in multiple cell lines. Oral administration of GSK2656157 to mice shows a dose- and time-dependent pharmacodynamic response in pancreas as measured by PERK auto-phosphorylation.

Price and Availability

GSK2656157, purity > 98%, is in stock. The same day shipping out after order is received.

Synonym:GSK2656157; GSK 2656157; GSK-2656157.

IUPAC/Chemical Name:1-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoroindolin-1-yl)-2-(6-methylpyridin-2-yl)ethanone

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)

SMILES Code:CC1=CC=CC(CC(N2CCC3=C2C=CC(C4=CN(C)C5=NC=NC(N)=C54)=C3F)=O)=N1

Technical Data

Additional Information

Twice daily dosing of GSK2656157 results in dose dependent inhibition of multiple human tumor xenografts growth in mice. Altered amino acid metabolism, decreased blood vessel density and vascular perfusion are potential mechanisms for the observed anti-tumor effect. However, despite its anti-tumor activity, given the on-target pharmacological effects of PERK inhibition on pancreatic function, development of any PERK inhibitor in human subjects would need to be cautiously pursued in cancer patients.   

References

1: Rojas-Rivera D, Delvaeye T, Roelandt R, Nerinckx W, Augustyns K, VandenabeeleP, Bertrand MJM. When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues on the specificity and use of GSK2606414 and GSK2656157. Cell Death Differ. 2017 Apr 28. doi: 10.1038/cdd.2017.58. [Epub ahead of print] PubMed PMID: 28452996.

2: Zhao Q, Che X, Zhang H, Tan G, Liu L, Jiang D, Zhao J, Xiang X, Sun X, He Z. Thioredoxin-Interacting Protein Mediates Apoptosis in Early Brain Injury after Subarachnoid Haemorrhage. Int J Mol Sci. 2017 Apr 18;18(4). pii: E854. doi: 10.3390/ijms18040854. PubMed PMID: 28420192.

3: Wang B, Ning H, Reed-Maldonado AB, Zhou J, Ruan Y, Zhou T, Wang HS, Oh BS, Banie L, Lin G, Lue TF. Low-Intensity Extracorporeal Shock Wave Therapy EnhancesBrain-Derived Neurotrophic Factor Expression through PERK/ATF4 Signaling Pathway. Int J Mol Sci. 2017 Feb 16;18(2). pii: E433. doi: 10.3390/ijms18020433. PubMed PMID: 28212323; PubMed Central PMCID: PMC5343967.

4: Nagasawa I, Kunimasa K, Tsukahara S, Tomida A. BRAF-mutated cells activate GCN2-mediated integrated stress response as a cytoprotective mechanism in response to vemurafenib. Biochem Biophys Res Commun. 2017 Jan 22;482(4):1491-1497. doi: 10.1016/j.bbrc.2016.12.062. Epub 2016 Dec 10. PubMed PMID: 27965097.

5: Liu B, Xia J, Chen Y, Zhang J. Sevoflurane-Induced Endoplasmic Reticulum Stress Contributes to Neuroapoptosis and BACE-1 Expression in the Developing Brain: The Role of eIF2α. Neurotox Res. 2017 Feb;31(2):218-229. doi: 10.1007/s12640-016-9671-z. Epub 2016 Sep 28. PubMed PMID: 27682474.

6: Ando T, Komatsu T, Naiki Y, Takahashi K, Yokochi T, Watanabe D, Koide N. GSK2656157, a PERK inhibitor, reduced LPS-induced IL-1β production through inhibiting Caspase 1 activation in macrophage-like J774.1 cells. ImmunopharmacolImmunotoxicol. 2016 Aug;38(4):298-302. doi: 10.1080/08923973.2016.1192191. Epub 2016 Jun 16. PubMed PMID: 27251848.

7: Gu N, Guo Q, Mao K, Hu H, Jin S, Zhou Y, He H, Oh Y, Liu C, Wu Q. Palmitate increases musclin gene expression through activation of PERK signaling pathway in C2C12 myotubes. Biochem Biophys Res Commun. 2015 Nov 20;467(3):521-6. doi: 10.1016/j.bbrc.2015.10.005. Epub 2015 Oct 9. PubMed PMID: 26449458.

8: Lv S, Sun EC, Xu QY, Zhang JK, Wu DL. Endoplasmic reticulum stress-mediated autophagy contributes to bluetongue virus infection via the PERK-eIF2α pathway. Biochem Biophys Res Commun. 2015 Oct 23;466(3):406-12. doi: 10.1016/j.bbrc.2015.09.039. Epub 2015 Sep 10. PubMed PMID: 26363458.

9: Jia XE, Ma K, Xu T, Gao L, Wu S, Fu C, Zhang W, Wang Z, Liu K, Dong M, Jing C, Ren C, Dong Z, Chen Y, Jin Y, Huang Q, Chang X, Deng M, Li L, Luo L, Zhu J, DangY, Chang HC, Zon LI, Zhou Y, Chen S, Pan W. Mutation of kri1l causes definitive hematopoiesis failure via PERK-dependent excessive autophagy induction. Cell Res. 2015 Aug;25(8):946-62. doi: 10.1038/cr.2015.81. Epub 2015 Jul 3. PubMed PMID: 26138676; PubMed Central PMCID: PMC4528055.

10: Axten JM, Romeril SP, Shu A, Ralph J, Medina JR, Feng Y, Li WH, Grant SW, Heerding DA, Minthorn E, Mencken T, Gaul N, Goetz A, Stanley T, Hassell AM, Gampe RT, Atkins C, Kumar R. Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development. ACS Med Chem Lett. 2013 Aug 12;4(10):964-8. doi: 10.1021/ml400228e. eCollection 2013 Oct 10. PubMed PMID: 24900593; PubMed Central PMCID: PMC4027568.

11: Krishnamoorthy J, Rajesh K, Mirzajani F, Kesoglidou P, Papadakis AI, Koromilas AE. Evidence for eIF2α phosphorylation-independent effects of GSK2656157, a novel catalytic inhibitor of PERK with clinical implications. CellCycle. 2014;13(5):801-6. doi: 10.4161/cc.27726. Epub 2014 Jan 8. PubMed PMID: 24401334; PubMed Central PMCID: PMC3979916.

12: 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. doi: 10.1158/0008-5472.CAN-12-3109. Epub 2013 Jan 18. PubMed PMID: 23333938.

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