GSK2656157
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MedKoo CAT#: 406230

CAS#: 1337532-29-2

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.


Chemical Structure

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GSK2656157
CAS# 1337532-29-2

Theoretical Analysis

MedKoo Cat#: 406230
Name: GSK2656157
CAS#: 1337532-29-2
Chemical Formula: C23H21FN6O
Exact Mass: 416.17609
Molecular Weight: 416.45
Elemental Analysis: C, 66.33; H, 5.08; F, 4.56; N, 20.18; O, 3.84

Price and Availability

Size Price Availability Quantity
10.0mg USD 90.0 Ready to ship
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 450.0 Ready to ship
200.0mg USD 850.0 Ready to ship
500.0mg USD 1550.0 Ready to ship
1.0g USD 2450.0 Ready to ship
2.0g USD 3850.0 Ready to ship
5.0g USD 6450.0 2 weeks
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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

Appearance: white to light yellow solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: GSK2656157 is an ATP-competitive inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) with an IC50 of 0.9 nM.
In vitro activity: When GyrB.PERK-expressing cells were treated with increasing concentrations of GSK2656157 in the presence of coumermycin, PERK inhibitor decreased eIF2α phosphorylation in a concentration-dependent manner (Fig. 1C). When GyrB.PKR cells were used, treatment with GSK2656157 did not have a similar robust effect on the inhibition of eIF2α phosphorylation, as in GyrB.PERK-expressing cells (Fig. 1D). These data indicated that GSK2656157 is a potent and rather specific PERK inhibitor in cells ectopically expressing a conditionally active form of the eIF2α kinase. Reference: Cell Cycle. 2014 Mar 1; 13(5): 801–806. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979916/
In vivo activity: STING phosphorylation in NeuN-positive cells was increased in the pericontusional cortex neurons of TBI mice compared with sham (Fig. 1B and Fig. 1-1C, D); however, phospho-STING expression was dramatically decreased after treatment with GSK2656157 following TBI (Fig. 1B and Fig. 1-1C,D). Similar to phospho-STING, phospho-TBK1 and phospho-IRF3 were also increased after TBI in the CX compared with sham (Fig. 1C,D, and Fig. 1-1E–H). TBI-mediated increase in phospho-TBK1 and phospho-IRF3 was considerably decreased by 3 d of GSK2656157 treatment following TBI (Fig. 1C,D, and Fig. 1-1E–H). Reference: J Neurosci. 2020 Jan 8; 40(2): 424–446. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948950/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 33.78 81.11
DMSO:PBS (pH 7.2) (1:3) 0.25 0.6
DMF 10.0 24.01
Ethanol 2.0 4.8
1M HCl 100.0 240.12

Preparing Stock Solutions

The following data is based on the product molecular weight 416.45 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Moore PC, Qi JY, Thamsen M, Ghosh R, Peng J, Gliedt MJ, Meza-Acevedo R, Warren RE, Hiniker A, Kim GE, Maly DJ, Backes BJ, Papa FR, Oakes SA. Parallel Signaling through IRE1α and PERK Regulates Pancreatic Neuroendocrine Tumor Growth and Survival. Cancer Res. 2019 Dec 15;79(24):6190-6203. doi: 10.1158/0008-5472.CAN-19-1116. Epub 2019 Oct 31. PMID: 31672843; PMCID: PMC6911642. 2. 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. Cell Cycle. 2014;13(5):801-6. doi: 10.4161/cc.27726. Epub 2014 Jan 8. PMID: 24401334; PMCID: PMC3979916. 3. Sen T, Saha P, Gupta R, Foley LM, Jiang T, Abakumova OS, Hitchens TK, Sen N. Aberrant ER Stress Induced Neuronal-IFNβ Elicits White Matter Injury Due to Microglial Activation and T-Cell Infiltration after TBI. J Neurosci. 2020 Jan 8;40(2):424-446. doi: 10.1523/JNEUROSCI.0718-19.2019. Epub 2019 Nov 6. PMID: 31694961; PMCID: PMC6948950. 4. Loeuillard E, El Mourabit H, Lei L, Lemoinne S, Housset C, Cadoret A. Endoplasmic reticulum stress induces inverse regulations of major functions in portal myofibroblasts during liver fibrosis progression. Biochim Biophys Acta Mol Basis Dis. 2018 Dec;1864(12):3688-3696. doi: 10.1016/j.bbadis.2018.10.008. Epub 2018 Oct 4. PMID: 30292633.
In vitro protocol: 1. Moore PC, Qi JY, Thamsen M, Ghosh R, Peng J, Gliedt MJ, Meza-Acevedo R, Warren RE, Hiniker A, Kim GE, Maly DJ, Backes BJ, Papa FR, Oakes SA. Parallel Signaling through IRE1α and PERK Regulates Pancreatic Neuroendocrine Tumor Growth and Survival. Cancer Res. 2019 Dec 15;79(24):6190-6203. doi: 10.1158/0008-5472.CAN-19-1116. Epub 2019 Oct 31. PMID: 31672843; PMCID: PMC6911642. 2. 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. Cell Cycle. 2014;13(5):801-6. doi: 10.4161/cc.27726. Epub 2014 Jan 8. PMID: 24401334; PMCID: PMC3979916.
In vivo protocol: 1. Sen T, Saha P, Gupta R, Foley LM, Jiang T, Abakumova OS, Hitchens TK, Sen N. Aberrant ER Stress Induced Neuronal-IFNβ Elicits White Matter Injury Due to Microglial Activation and T-Cell Infiltration after TBI. J Neurosci. 2020 Jan 8;40(2):424-446. doi: 10.1523/JNEUROSCI.0718-19.2019. Epub 2019 Nov 6. PMID: 31694961; PMCID: PMC6948950. 2. Loeuillard E, El Mourabit H, Lei L, Lemoinne S, Housset C, Cadoret A. Endoplasmic reticulum stress induces inverse regulations of major functions in portal myofibroblasts during liver fibrosis progression. Biochim Biophys Acta Mol Basis Dis. 2018 Dec;1864(12):3688-3696. doi: 10.1016/j.bbadis.2018.10.008. Epub 2018 Oct 4. PMID: 30292633.

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1: Rojas-Rivera D, Delvaeye T, Roelandt R, Nerinckx W, Augustyns K, Vandenabeele P, 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 Enhances Brain-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. Immunopharmacol Immunotoxicol. 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, Dang Y, 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. Cell Cycle. 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.



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.