eukaryotic translation initiation factor 2 alpha kinase 3 | PEK subfamily | IUPHAR/BPS Guide to PHARMACOLOGY

eukaryotic translation initiation factor 2 alpha kinase 3

Target id: 2017

Nomenclature: eukaryotic translation initiation factor 2 alpha kinase 3

Abbreviated Name: PERK

Family: PEK subfamily

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for eukaryotic translation initiation factor 2 alpha kinase 3 in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1116 2p12 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 4 q32 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
BRENDA
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 2.7.11.1

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
GSK2606414 Hs Inhibition 9.4 pIC50 1
pIC50 9.4 (IC50 4x10-10 M) [1]
GSK2656157 Hs Inhibition 9.1 pIC50 2
pIC50 9.1 (IC50 8x10-10 M) [2]
Description: Biochemical activity
Clinically-Relevant Mutations and Pathophysiology
Disease:  Epiphyseal dysplasia, multiple, with early-onset diabetes mellitus
Synonyms: Wolcott-Rallison syndrome [Orphanet: ORPHA1667]
OMIM: 226980
Orphanet: ORPHA1667
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 [5]. Inhibition of the UPR is considered to provide a novel intervention point for diseases including Alzheimer's and other dementias, and Parkinson's disease [4]. GSK2606414 is a PERK inhibitor that has shown promising effects in animal models [4], 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 [3] (DOI: https://doi.org/10.1093/brain/awx074). A second potential lead, dibenzoylmethane was also discovered in this study.

References

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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. Halliday M, Redford 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, Online ahead of print.

4. 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]

5. 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 20/04/2017. Accessed on 16/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2017.