GSK2606414
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    WARNING: This product is for research use only, not for human or veterinary use.

MedKoo CAT#: 406393

CAS#: 1337531-36-8

Description: GSK2606414 is an orally available, potent, and selective PERK inhibitor. GSK2606414 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors.

Chemical Structure

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GSK2606414
CAS# 1337531-36-8
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 406393
Name: GSK2606414
CAS#: 1337531-36-8
Chemical Formula: C24H20F3N5O
Exact Mass: 451.16
Molecular Weight: 451.440
Elemental Analysis: C, 63.85; H, 4.47; F, 12.63; N, 15.51; O, 3.54

Price and Availability

Size Price Availability Quantity
10mg USD 90 Ready to ship
25mg USD 150 Ready to ship
50mg USD 250 Ready to ship
100mg USD 450 Ready to ship
200mg USD 750 Ready to ship
500mg USD 1650 Ready to ship
1g USD 2950 Ready to ship
2g USD 5250 Ready to ship
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Synonym: GSK2606414; GSK-2606414; GSK 2606414; GSK PERK Inhibitor.

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

InChi Key: SIXVRXARNAVBTC-UHFFFAOYSA-N

InChi Code: InChI=1S/C24H20F3N5O/c1-31-12-18(21-22(28)29-13-30-23(21)31)15-5-6-19-16(11-15)7-8-32(19)20(33)10-14-3-2-4-17(9-14)24(25,26)27/h2-6,9,11-13H,7-8,10H2,1H3,(H2,28,29,30)

SMILES Code: FC(C1=CC(CC(N2CCC3=C2C=CC(C4=CN(C)C5=NC=NC(N)=C54)=C3)=O)=CC=C1)(F)F

Appearance: white 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

More Info:      The chemical structures of GSK2606414  and GSK2656157 are very similar. The following graphic is a side-by-side comparison.   

Biological target: GSK2606414 is a protein kinase R-like endoplasmic reticulum kinase (PERK) inhibitor with an IC50 of 0.4 nM.
In vitro activity: The effects of GSK2606414 on proliferation, apoptosis, and the expression of activating transcription factor 4 (ATF4), CCAAT/enhancer‑binding protein homologous protein (CHOP) and vascular endothelial growth factor (VEGF) in human retinal pigment epithelial (RPE) cells under endoplasmic reticulum (ER) stress were investigated. GSK2606414 treatment inhibited RPE cell proliferation in a dose‑dependent manner, however it did not induce apoptosis. In addition, GSK2606414 treatment inhibited eIF2α phosphorylation and reduced CHOP and VEGF mRNA expression levels in RPE cells under TG (thapsigargin) induced ER stress. Reference: Mol Med Rep. 2017 May;15(5):3105-3110. https://www.spandidos-publications.com/mmr/15/5/3105
In vivo activity: The roles of the PERK signaling pathway in the secondary brain injury (SBI) induced by intracerebral hemorrhage (ICH) and its potential mechanisms were investigated. Sprague-Dawley rats were used to establish ICH models by injecting autologous blood (100 μl). The PERK inhibitor GSK2606414 was injected intracerebroventricularly at 1 h after ICH and the eIF2α dephosphorylation inhibitor salubrinal, as an agonist of PERK downstream signaling pathway, was injected intraperitoneally at 30 min before ICH, respectively. It was revealed that with the treatment of GSK2606414 and salubrinal, the protein levels of p-eIF2α and ATF-4 were decreased and increased compared with ICH + vehicle (GSK2606414) and ICH + vehicle (salubrinal) group respectively (Figure 3A). Reference: Front Neurosci. 2018 Feb 28;12:111. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835756/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMF 10.0 22.15
DMSO 55.4 122.67
DMSO:PBS (pH 7.2) (1:3) 0.3 0.55
Ethanol 11.5 25.47

Preparing Stock Solutions

The following data is based on the product molecular weight 451.44 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. Jiang X, Wei Y, Zhang T, Zhang Z, Qiu S, Zhou X, Zhang S. Effects of GSK2606414 on cell proliferation and endoplasmic reticulum stress‑associated gene expression in retinal pigment epithelial cells. Mol Med Rep. 2017 May;15(5):3105-3110. doi: 10.3892/mmr.2017.6418. Epub 2017 Mar 30. PMID: 28358434. 2. Meng C, Zhang J, Dang B, Li H, Shen H, Li X, Wang Z. PERK Pathway Activation Promotes Intracerebral Hemorrhage Induced Secondary Brain Injury by Inducing Neuronal Apoptosis Both in Vivo and in Vitro. Front Neurosci. 2018 Feb 28;12:111. doi: 10.3389/fnins.2018.00111. PMID: 29541018; PMCID: PMC5835756.
In vitro protocol: 1. Jiang X, Wei Y, Zhang T, Zhang Z, Qiu S, Zhou X, Zhang S. Effects of GSK2606414 on cell proliferation and endoplasmic reticulum stress‑associated gene expression in retinal pigment epithelial cells. Mol Med Rep. 2017 May;15(5):3105-3110. doi: 10.3892/mmr.2017.6418. Epub 2017 Mar 30. PMID: 28358434.
In vivo protocol: 1. Meng C, Zhang J, Dang B, Li H, Shen H, Li X, Wang Z. PERK Pathway Activation Promotes Intracerebral Hemorrhage Induced Secondary Brain Injury by Inducing Neuronal Apoptosis Both in Vivo and in Vitro. Front Neurosci. 2018 Feb 28;12:111. doi: 10.3389/fnins.2018.00111. PMID: 29541018; PMCID: PMC5835756.

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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: Wen L, Xiao B, Shi Y, Han F. PERK signalling pathway mediates single prolonged stress-induced dysfunction of medial prefrontal cortex neurons. Apoptosis. 2017 Jun;22(6):753-768. doi: 10.1007/s10495-017-1371-5. PubMed PMID: 28391375.

3: Jiang X, Wei Y, Zhang T, Zhang Z, Qiu S, Zhou X, Zhang S. Effects of GSK2606414 on cell proliferation and endoplasmic reticulum stress associated gene expression in retinal pigment epithelial cells. Mol Med Rep. 2017 May;15(5):3105-3110. doi: 10.3892/mmr.2017.6418. Epub 2017 Mar 30. PubMed PMID: 28358434.

4: Zhang J, Feng Z, Wang C, Zhou H, Liu W, Kanchana K, Dai X, Zou P, Gu J, Cai L, Liang G. Curcumin derivative WZ35 efficiently suppresses colon cancer progression through inducing ROS production and ER stress-dependent apoptosis. Am J Cancer Res. 2017 Feb 1;7(2):275-288. eCollection 2017. PubMed PMID: 28337376; PubMed Central PMCID: PMC5336501.

5: Sharma R, Quilty F, Gilmer JF, Long A, Byrne AM. Unconjugated secondary bile acids activate the unfolded protein response and induce golgi fragmentation via a src-kinase-dependant mechanism. Oncotarget. 2017 Jan 3;8(1):967-978. doi: 10.18632/oncotarget.13514. PubMed PMID: 27888615; PubMed Central PMCID: PMC5352210.

6: Abhishek K, Sardar AH, Das S, Kumar A, Ghosh AK, Singh R, Saini S, Mandal A, Verma S, Kumar A, Purkait B, Dikhit MR, Das P. Phosphorylation of Translation Initiation Factor 2-Alpha in Leishmania donovani under Stress Is Necessary for Parasite Survival. Mol Cell Biol. 2016 Dec 19;37(1). pii: e00344-16. Print 2017 Jan 1. PubMed PMID: 27736773; PubMed Central PMCID: PMC5192082.

7: Wu WS, Chien CC, Chen YC, Chiu WT. Protein Kinase RNA-Like Endoplasmic Reticulum Kinase-Mediated Bcl-2 Protein Phosphorylation Contributes to Evodiamine-Induced Apoptosis of Human Renal Cell Carcinoma Cells. PLoS One. 2016 Aug 2;11(8):e0160484. doi: 10.1371/journal.pone.0160484. eCollection 2016. PubMed PMID: 27483435; PubMed Central PMCID: PMC4970736.

8: Celardo I, Costa AC, Lehmann S, Jones C, Wood N, Mencacci NE, Mallucci GR, Loh SH, Martins LM. Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease. Cell Death Dis. 2016 Jun 23;7(6):e2271. doi: 10.1038/cddis.2016.173. PubMed PMID: 27336715; PubMed Central PMCID: PMC5143399.

9: Guthrie LN, Abiraman K, Plyler ES, Sprenkle NT, Gibson SA, McFarland BC, Rajbhandari R, Rowse AL, Benveniste EN, Meares GP. Attenuation of PKR-like ER Kinase (PERK) Signaling Selectively Controls Endoplasmic Reticulum Stress-induced Inflammation Without Compromising Immunological Responses. J Biol Chem. 2016 Jul 22;291(30):15830-40. doi: 10.1074/jbc.M116.738021. Epub 2016 May 23. PubMed PMID: 27226638; PubMed Central PMCID: PMC4957064.

10: Zhou Y, Qi B, Gu Y, Xu F, Du H, Li X, Fang W. Porcine Circovirus 2 Deploys PERK Pathway and GRP78 for Its Enhanced Replication in PK-15 Cells. Viruses. 2016 Feb 20;8(2). pii: E56. doi: 10.3390/v8020056. PubMed PMID: 26907328; PubMed Central PMCID: PMC4776210.

11: Chen TC, Chien CC, Wu MS, Chen YC. Evodiamine from Evodia rutaecarpa induces apoptosis via activation of JNK and PERK in human ovarian cancer cells. Phytomedicine. 2016 Jan 15;23(1):68-78. doi: 10.1016/j.phymed.2015.12.003. Epub 2015 Dec 22. PubMed PMID: 26902409.

12: Yan F, Cao S, Li J, Dixon B, Yu X, Chen J, Gu C, Lin W, Chen G. Pharmacological Inhibition of PERK Attenuates Early Brain Injury After Subarachnoid Hemorrhage in Rats Through the Activation of Akt. Mol Neurobiol. 2017 Apr;54(3):1808-1817. doi: 10.1007/s12035-016-9790-9. Epub 2016 Feb 18. PubMed PMID: 26887383.

13: Radford H, Moreno JA, Verity N, Halliday M, Mallucci GR. PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathol. 2015 Nov;130(5):633-42. doi: 10.1007/s00401-015-1487-z. Epub 2015 Oct 8. PubMed PMID: 26450683; PubMed Central PMCID: PMC4612323.

14: Johari YB, Estes SD, Alves CS, Sinacore MS, James DC. Integrated cell and process engineering for improved transient production of a "difficult-to-express" fusion protein by CHO cells. Biotechnol Bioeng. 2015 Dec;112(12):2527-42. doi: 10.1002/bit.25687. Epub 2015 Sep 7. PubMed PMID: 26126657.

15: Jamison S, Lin Y, Lin W. Pancreatic endoplasmic reticulum kinase activation promotes medulloblastoma cell migration and invasion through induction of vascular endothelial growth factor A. PLoS One. 2015 Mar 20;10(3):e0120252. doi: 10.1371/journal.pone.0120252. eCollection 2015. PubMed PMID: 25794107; PubMed Central PMCID: PMC4368580.

16: Halliday M, Radford H, Sekine Y, Moreno J, Verity N, le Quesne J, Ortori CA, Barrett DA, Fromont C, Fischer PM, Harding HP, Ron D, Mallucci GR. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis. 2015 Mar 5;6:e1672. doi: 10.1038/cddis.2015.49. PubMed PMID: 25741597; PubMed Central PMCID: PMC4385927.

17: Moon HS, Kim B, Gwak H, Suh DH, Song YS. Autophagy and protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha kinase (eIF2α) pathway protect ovarian cancer cells from metformin-induced apoptosis. Mol Carcinog. 2016 Apr;55(4):346-56. doi: 10.1002/mc.22284. Epub 2015 Feb 7. PubMed PMID: 25663310.

18: Lin LC, Sibille E. Somatostatin, neuronal vulnerability and behavioral emotionality. Mol Psychiatry. 2015 Mar;20(3):377-87. doi: 10.1038/mp.2014.184. Epub 2015 Jan 20. PubMed PMID: 25600109; PubMed Central PMCID: PMC4355106.

19: Ounallah-Saad H, Sharma V, Edry E, Rosenblum K. Genetic or pharmacological reduction of PERK enhances cortical-dependent taste learning. J Neurosci. 2014 Oct 29;34(44):14624-32. doi: 10.1523/JNEUROSCI.2117-14.2014. PubMed PMID: 25355215.

20: 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.


Ghaddar N, Wang S, Woodvine B, Krishnamoorthy J, van Hoef V, Darini C, Kazimierczak U, Ah-Son N, Popper H, Johnson M, Officer L, Teodósio A, Broggini M, Mann KK, Hatzoglou M, Topisirovic I, Larsson O, Le Quesne J, Koromilas AE. The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer. Nat Commun. 2021 Jul 30;12(1):4651. doi: 10.1038/s41467-021-24661-0. PMID: 34330898; PMCID: PMC8324901.