2017
DOI: 10.1038/cdd.2017.58
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When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues on the specificity and use of GSK2606414 and GSK2656157

Abstract: Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes a state of cellular stress known as ER stress. The cells respond to ER stress by activating the unfolded protein response (UPR), a signaling network emerging from the ER-anchored receptors IRE1α, PERK and ATF6. The UPR aims at restoring ER protein-folding homeostasis, but turns into a toxic signal when the stress is too severe or prolonged. Recent studies have demonstrated links between the UPR and inflammation. Consequently, small mole… Show more

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Cited by 158 publications
(125 citation statements)
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References 43 publications
(75 reference statements)
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“…Interestingly, oral administration of GSK2606414 alleviated neurodegeneration in tau transgenic mice [140]. However, a recent report suggested that GSK2606414 has a higher affinity for RIP kinases, in addition to generating serious side effects due to pancreatic toxicity [141]. In contrast, the administration of ISRIB provided neuroprotection in a model of prion disease while not triggering any pancreatic toxicity [50].…”
Section: Targeting the Upr For Therapeutic Inerventionmentioning
confidence: 99%
“…Interestingly, oral administration of GSK2606414 alleviated neurodegeneration in tau transgenic mice [140]. However, a recent report suggested that GSK2606414 has a higher affinity for RIP kinases, in addition to generating serious side effects due to pancreatic toxicity [141]. In contrast, the administration of ISRIB provided neuroprotection in a model of prion disease while not triggering any pancreatic toxicity [50].…”
Section: Targeting the Upr For Therapeutic Inerventionmentioning
confidence: 99%
“…Conversely, GSK-PKI treatment mildly increased apoptosis and dampened growth rate in cultured INS-1 cells (Fig 4B and C). This discrepancy may stem from pathway compensation in PERK KO cells or off-target GSK-PKI effects (48), but the aggregate effect is modest under low ER stress.…”
Section: Induced Apoptosis In Vitromentioning
confidence: 99%
“…PERK inhibition by these small molecules induced pancreatic β-cell toxicity, similar to what has been seen in the PERK knockout mouse, indicating more sophisticated methods to deliver these inhibitors are required (140).…”
Section: Amg Perk44mentioning
confidence: 77%