GSK2606414 | PERK inhibitor

GSK2606414 (1337531-36-8) is a potent (IC₅₀ = 0.4 nM) and selective (against a panel of 294 kinases) inhibitor of protein kinase R-like endoplasmic reticulum kinase (PERK), an important effector of the unfolded protein response (UPR).¹ It prevented neurodegeneration in a mouse model of frontotemporal dementia² and rodent models of Parkinsons disease via modulation of the UPR³. GSK2606414 has been reported to be a potent inhibitor of RIPK1 (IC₅₀ = 18 nM).⁴ It has also displayed neuroprotective effects in various models of stroke.^5-7

References/Citations:

1. Axten 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]pyrimidine-4-amine (GSK2606414); J. Med. Chem., 55 7193
2. Radford et al. (2015), PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia; Acta Neuropathol., 130 633
3. Mercado et al. (2018), Targeting PERK signaling with the small molecules GSK2606414 prevents neurodegeneration in a model of Parkinson’s disease; Neurobiol. Dis., 112 136
4. 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
5. Yan et al. (2017), Pharmacological Inhibition of PERK Attenuates Early Brain Injury After Subarachnoid Hemorrhage in Rats Through the Activation of Akt; Mol. Neurobiol., 54 1808
6. Meng et al. (2018), PERK Pathway Activation Promotes Intracerebral Hemorrhage Induced Secondary Brain Injury by Inducing Apoptosis Both in Vivo and in Vitro; Front. Neurosci., 12 111
7. Dhir et al. (2023), PERK inhibitor, GSK2606414, ameliorates neuropathological damage, memory and motor functional impairments in cerebral ischemia via PERK/p-eIFα/ATP/CHOP signaling; Metab. Brain Dis., online ahead of print