1337532-29-2

Usage

Uses

Used in Oncology:
GSK2656157 is used as an anti-tumor agent for its ability to inhibit the growth of multiple human tumor xenografts in mice. It is particularly effective due to its ATP-competitive and highly selective nature, targeting the PKR-like endoplasmic reticulum kinase (PERK) enzyme activity.
Used in Neurology:
GSK2656157 is used as a neuroprotective agent for its ability to prevent the loss of dendritic spines and rescue memory deficits after traumatic brain injury.
Used in Endocrinology:
GSK2656157 is used as a therapeutic agent for type 2 diabetes mellitus, as it has been shown to enhance glucose-stimulated insulin secretion in a mouse model.
Used in Angiogenesis Research:
GSK2656157 is used as an anti-angiogenic agent for its demonstrated anti-angiogenic activity, which can be beneficial in the development of treatments for conditions where abnormal blood vessel formation is a concern.

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].

References

Atkins et al. (2013) Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity; Cancer Res. 73 1993 Axten et al. (2014) Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development; ACS Med. Chem. Lett. 4 964 Rojas-Rivera et al. (2017) 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. 24 1100 Sen et al. (2017) Activation of PERK Elicits Memory Impairment through Inactivation of CREB and Downregulation of PSD95 After Traumatic Brain Injury; Neurosci. 37 5900 Kim et al. (2019) Specific PERK inhibitors enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes; Metabolism, 97 87

Upstream product

• 552866-98-5 2,3-dihydro-4-fluoro-1H-indole 
• 387-43-9 4-fluoroindole 
• 1037075-45-8 1,1-dimethylethyl 4-fluoro-2,3-dihydro-1H-indole-1-carboxylate 
• 1337533-33-1 1,1-dimethylethyl 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate 
• 18368-63-3 6-chloro-2-picoline 
• 1337533-49-9 1,1-dimethylethyl (6-methyl-2-pyridinyl)acetate 
• 1337533-31-9 1,1-dimethylethyl 5-bromo-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate 
• 1337533-32-0 1,1-dimethylethyl 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate 

Relevant academic research and scientific papers

COMPOUNDS AND METHODS FOR TREATING INSULIN RESISTANCE SYNDROME

The present invention relates to a method of treating or preventing insulin resistance syndrome in an animal body by administering an inhibitor of protein kinase RNA-like endoplasmic reticulum kinase (PERK) gene, or a functional variant thereof, or an inhibitor of PERK protein or a functional variant thereof or a method of reducing activity of transcription factors of the FOXO family (Foxo 1, 3a, 4 and 6) by administering an inhibitor of protein kinase RNA-like endoplasmic reticulum kinase (PERK) gene, or a functional variant thereof, or an inhibitor of PERK protein or a functional variant thereof. The present invention also relates to different compounds and methods for using PERK gene or PERK protein.

Discovery of GSK2656157: An optimized PERK inhibitor selected for preclinical development

We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.