Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)
- PMID: 22827572
- DOI: 10.1021/jm300713s
Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)
Abstract
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. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.
Similar articles
-
Protein kinase R(PKR)-like endoplasmic reticulum kinase (PERK) inhibitors: a patent review (2010-2015).Expert Opin Ther Pat. 2017 Jan;27(1):37-48. doi: 10.1080/13543776.2017.1238072. Epub 2016 Sep 23. Expert Opin Ther Pat. 2017. PMID: 27646439 Review.
-
Tumor progression and the different faces of the PERK kinase.Oncogene. 2016 Mar 10;35(10):1207-15. doi: 10.1038/onc.2015.178. Epub 2015 Jun 1. Oncogene. 2016. PMID: 26028033 Free PMC article. Review.
-
Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors.Bioorg Med Chem. 2014 Sep 1;22(17):4998-5012. doi: 10.1016/j.bmc.2014.06.025. Epub 2014 Jun 21. Bioorg Med Chem. 2014. PMID: 25009002
-
Novel inhibitors of epidermal growth factor receptor: (4-(Arylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(1H-indol-2-yl)methanones and (1H-indol-2-yl)(4-(phenylamino)thieno[2,3-d]pyrimidin-6-yl)methanones.Bioorg Med Chem. 2012 Jan 1;20(1):125-36. doi: 10.1016/j.bmc.2011.11.023. Epub 2011 Nov 20. Bioorg Med Chem. 2012. PMID: 22169601
-
Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold.J Med Chem. 2011 Dec 8;54(23):8030-50. doi: 10.1021/jm2008634. Epub 2011 Nov 4. J Med Chem. 2011. PMID: 22003817
Cited by
-
Therapeutic Potential of Targeting the PERK Signaling Pathway in Ischemic Stroke.Pharmaceuticals (Basel). 2024 Mar 8;17(3):353. doi: 10.3390/ph17030353. Pharmaceuticals (Basel). 2024. PMID: 38543139 Free PMC article. Review.
-
Protein-rich foods, sea foods, and gut microbiota amplify immune responses in chronic diseases and cancers - Targeting PERK as a novel therapeutic strategy for chronic inflammatory diseases, neurodegenerative disorders, and cancer.Pharmacol Ther. 2024 Mar;255:108604. doi: 10.1016/j.pharmthera.2024.108604. Epub 2024 Feb 13. Pharmacol Ther. 2024. PMID: 38360205 Review.
-
Emerging mechanisms of the unfolded protein response in therapeutic resistance: from chemotherapy to Immunotherapy.Cell Commun Signal. 2024 Jan 31;22(1):89. doi: 10.1186/s12964-023-01438-0. Cell Commun Signal. 2024. PMID: 38297380 Free PMC article. Review.
-
Mammalian integrated stress responses in stressed organelles and their functions.Acta Pharmacol Sin. 2024 Jun;45(6):1095-1114. doi: 10.1038/s41401-023-01225-0. Epub 2024 Jan 24. Acta Pharmacol Sin. 2024. PMID: 38267546 Review.
-
Direct neuronal reprogramming of NDUFS4 patient cells identifies the unfolded protein response as a novel general reprogramming hurdle.Neuron. 2024 Apr 3;112(7):1117-1132.e9. doi: 10.1016/j.neuron.2023.12.020. Epub 2024 Jan 23. Neuron. 2024. PMID: 38266647 Free PMC article.
MeSH terms
Substances
Associated data
- Actions
- Actions
LinkOut - more resources
Full Text Sources
Other Literature Sources
Chemical Information
Molecular Biology Databases