GSK2656157 Chemical Properties

Melting point:

194-196°C

Boiling point:

744.6±60.0 °C(Predicted)

Density 

1.43±0.1 g/cm3(Predicted)

storage temp. 

-20°C

solubility 

Soluble in DMSO (10 mg/ml with warming)

form 

solid

pka

5.32±0.30(Predicted)

color 

White

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month.

GSK2656157 Usage And Synthesis

Description

GSK2656157 (1337532-29-2) is a potent (IC50 = 0.9 nM) and selective (over 300 kinases) inhibitor of protein kinase RNA-like endoplasmic reticulum kinase (PERK).1,2? Inhibited growth of multiple human tumor xenografts in mice. GSK2656157 has also been found to potently inhibit RIPK1 (IC50 = 69 nM) and TNF-mediated RIPK1 kinase-dependent cell death in mouse embryonic fibroblasts.3 It prevented the loss of dendritic spines and rescued memory deficits after traumatic brain injury.4? GSK2656157 also enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes mellitus.5

Uses

GSK2656157 is an ATP-competitive and highly selective inhibitor of PKR-like endoplasmic reticulum kinase (PERK) enzyme activity. GSK2656157 also has anti-tumor and anti-angiogenic activity.

Definition

ChEBI: GSK2656157 is a pyrrolopyrimidine that is 7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine which has been substituted at position 5 by a 4-fluoro-2,3-dihydro-1H-indol-5-yl group, the nitrogen of which has been acylated by a (6-methylpyridin-2-yl)acetyl group. An orally bioavailable PERK inhibitor. It has a role as an EC 3.1.3.48 (protein-tyrosine-phosphatase) inhibitor, a PERK inhibitor and an antineoplastic agent. It is a pyrrolopyrimidine, a biaryl, a member of indoles, a member of methylpyridines, an organofluorine compound and a tertiary carboxamide.

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].

IC 50

EIF2AK3 (PERK): 0.9 nM (IC₅₀); EIF2AK1 (HRI): 460 nM (IC₅₀); BRK: 905 nM (IC₅₀); EIF2AK2 (PKR): 905 nM (IC₅₀); MEKK3: 954 nM (IC₅₀); Aurora B: 1259 nM (IC₅₀); KHS: 1764 nM (IC₅₀); LCK: 2344 nM (IC₅₀); MLK2: 2796 nM (IC₅₀); MEKK3: 2847 nM (IC₅₀); ALK5: 3020 nM (IC₅₀); MLCK2: 3039 nM (IC₅₀); EIF2AK4(GCN2): 3162 nM (IC₅₀); c-MER: 3431 nM (IC₅₀); PI3Kγ: 3802 nM (IC₅₀); WNK3: 5951 nM (IC₅₀); LRRK2: 6918 nM (IC₅₀); ROCK1: 7244 nM (IC₅₀); MSK1: 8985 nM (IC₅₀); NEK1: 9807 nM (IC₅₀); AXL: 9808 nM (IC₅₀); JAK2: 24547 nM (IC₅₀)

References

[1] CHARITY ATKINS. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity.[J]. Cancer research, 2013, 73 6: 1993-2002. DOI:10.1158/0008-5472.can-12-3109
[2] JEFFREY M. AXTEN*. Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development[J]. ACS Medicinal Chemistry Letters, 2013, 4 10: 964-968. DOI:10.1021/ml400228e
[3] DIEGO ROJAS-RIVERA. When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues on the specificity and use of GSK2606414 and GSK2656157[J]. Cell Death and Differentiation, 2017, 24 6: 1100-1110. DOI:10.1038/cdd.2017.58
[4] TANUSREE SEN. Activation of PERK Elicits Memory Impairment through Inactivation of CREB and Downregulation of PSD95 After Traumatic Brain Injury.[J]. Journal of Neuroscience, 2017, 37 24: 5900-5911. DOI:10.1523/jneurosci.2343-16.2017
[5] MIN JOO KIM . Specific PERK inhibitors enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes[J]. Metabolism: clinical and experimental, 2019, 97: Pages 87-91. DOI:10.1016/j.metabol.2018.12.007

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