eukaryotic translation initiation factor 2 alpha kinase 3
Target not currently curated in GtoImmuPdb
Target id: 2017
Nomenclature: eukaryotic translation initiation factor 2 alpha kinase 3
Abbreviated Name: PERK
Family: PEK subfamily
Contents:
Gene and Protein Information  |
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| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 1 | 1116 | 2p11.2 | EIF2AK3 | eukaryotic translation initiation factor 2 alpha kinase 3 | |
| Mouse | 1 | 1114 | 6 C1 | Eif2ak3 | eukaryotic translation initiation factor 2 alpha kinase 3 | |
| Rat | 1 | 1108 | 4q31 | Eif2ak3 | eukaryotic translation initiation factor 2 alpha kinase 3 | |
| Previous and Unofficial Names |
| PERK | pancreatic eIF2-alpha kinase | PEK | PRKR-like endoplasmic reticulum kinase |
| Database Links |
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| Alphafold | Q9NZJ5 (Hs), Q9Z2B5 (Mm), Q9Z1Z1 (Rn) |
| BRENDA | 2.7.11.1 |
| ChEMBL Target | CHEMBL6030 (Hs), CHEMBL4105946 (Rn) |
| Ensembl Gene | ENSG00000172071 (Hs), ENSMUSG00000031668 (Mm), ENSRNOG00000006069 (Rn) |
| Entrez Gene | 9451 (Hs), 13666 (Mm), 29702 (Rn) |
| Human Protein Atlas | ENSG00000172071 (Hs) |
| KEGG Enzyme | 2.7.11.1 |
| KEGG Gene | hsa:9451 (Hs), mmu:13666 (Mm), rno:29702 (Rn) |
| OMIM | 604032 (Hs) |
| Orphanet | ORPHA121317 (Hs) |
| Pharos | Q9NZJ5 (Hs) |
| RefSeq Nucleotide | NM_004836 (Hs), NM_010121 (Mm), NM_031599 (Rn) |
| RefSeq Protein | NP_004827 (Hs), NP_034251 (Mm), NP_113787 (Rn) |
| UniProtKB | Q9NZJ5 (Hs), Q9Z2B5 (Mm), Q9Z1Z1 (Rn) |
| Wikipedia | EIF2AK3 (Hs) |
| Enzyme Reaction |
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Download all structure-activity data for this target as a CSV file 
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Immuno Process Associations | ||
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| Clinically-Relevant Mutations and Pathophysiology
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| General Comments |
| PERK is one of the three mediators of the unfolded protein response (UPR). PERK drives the arrest of protein production in response to rising levels of misfolded proteins in the endoplasmic reticulum, a response active in and contributing to neurodegeneration in brain diseases characterised by protein-misfolding [6]. Inhibition of the UPR is considered to provide a novel intervention point for diseases including Alzheimer's and other dementias, and Parkinson's disease [5]. GSK2606414 is a PERK inhibitor that has shown promising effects in animal models [5], but has unfavouable toxicology. A screen of bioactive compounds already used clinically as inhibitors of the UPR, has identified the approved antidepressant trazodone which is is expected to be taken forward relatively quickly to clinical trial (as it already has en established safety profile in patients) to evaluate its ability to delay disease progression in selected patient groups [4] (DOI: https://doi.org/10.1093/brain/awx074). A second potential lead, dibenzoylmethane was also discovered in this study. |
References
1. Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WH, Heerding DA, Minthorn E, Mencken T et al.. (2012) 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). J Med Chem, 55 (16): 7193-207. [PMID:22827572]
2. Axten JM, Romeril SP, Shu A, Ralph J, Medina JR, Feng Y, Li WH, Grant SW, Heerding DA, Minthorn E et al.. (2013) Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development. ACS Med Chem Lett, 4 (10): 964-8. [PMID:24900593]
3. Calvo V, Surguladze D, Li AH, Surman MD, Malibhatla S, Bandaru M, Jonnalagadda SK, Adarasandi R, Velmala M, Singireddi DRP et al.. (2021) Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors. Bioorg Med Chem Lett, 43: 128058. [PMID:33895276]
4. Halliday M, Radford H, Zents KAM, Molloy C, Moreno JA, Verity NC, Smith E, Ortori CA, Barrett DA, Bushell M et al.. (2017) Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain, 140 (6): 1768-1783. [PMID:28430857]
5. Radford H, Moreno JA, Verity N, Halliday M, Mallucci GR. (2015) PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathol, 130 (5): 633-42. [PMID:26450683]
6. Smith HL, Mallucci GR. (2016) The unfolded protein response: mechanisms and therapy of neurodegeneration. Brain, 139 (Pt 8): 2113-21. [PMID:27190028]
How to cite this page
PEK subfamily: eukaryotic translation initiation factor 2 alpha kinase 3. Last modified on 21/03/2024. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2017.
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