GSK2606414

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Background

GSK2606414 is a selective inhibitor of PERK with IC50 value of 0.4nM.[1]PERK (PRKR-like endoplasmic reticulum kinase or protein kinase R (PKR)-like endoplasmic reticulum kinase) is also known as EIF2AK3 (Eukaryotic translation initiation factor 2-alpha kinase 3). PERK is encoded by EIF2AK3 gene. It belongs to type I membrane protein family. It located in the ER (endoplasmic reticulum) and is induced by ER stress which is caused from malfolded proteins. It causes the inactive of EIF2 (eukaryotic translation-initiation factor 2) by phosphorylating the alpha subunit. PERK can lead to repression of global protein synthesis and a rapid reduction of translational initiation. PERK has been identified to interact with NFE2L2 and DNAJC3. PERK mutation is related to WRS (Wolcott-Rallison syndrome) which is a autosomal recessive disorder with multiple epiphyseal dysplasia,infancy-onset diabetes mellitus, osteopenia, mental retardation, and hepatic and renal dysfunction. [2]GSK2606414 inhibits the activity of PERK with IC50 of 0.4 nM by measuring the cytoplasmic PERK domain phosphorylation. GSK2606414 directly bind to PERK as measured in X-ray structure. GSK2606414 completely inhibit PERK phosphorylation at 30 nM in A549 cells. GSK2606414 has selective inhibition effect on PERK compared to a panel of 294 kinases. There only 20 protein kinases except PERK inhibited >85% by GSK2606414 at 10 μM. GSK2606414 inhibited tumor growth with a dose-dependent manner from 50 to 150 mg/kg in mice bearing pancreatic human BxPC3 tumors.[1]

[1]. Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WH, Heerding DA, Minthorn E, Mencken T et al: Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[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):7193-7207.
[2]. Shi Y, An J, Liang J, Hayes SE, Sandusky GE, Stramm LE, Yang NN: Characterization of a mutant pancreatic eIF-2alpha kinase, PEK, and co-localization with somatostatin in islet delta cells. J Biol Chem 1999, 274(9):5723-5730.