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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

(2017) CELL DEATH AND DIFFERENTIATION. 24(6). p.1100-1110
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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 IRE1 alpha, 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 molecule inhibitors of IRE1 alpha and PERK have become attractive tools for the potential therapeutic manipulation of the UPR in inflammatory conditions. TNF is a master pro-inflammatory cytokine that drives inflammation either directly by promoting gene activation, or indirectly by inducing RIPK1 kinase-dependent cell death, in the form of apoptosis or necroptosis. To evaluate the potential contribution of the UPR to TNF-induced cell death, we tested the effects of two commonly used PERK inhibitors, GSK2606414 and GSK2656157. Surprisingly, we observed that both compounds completely repressed TNF-mediated RIPK1 kinase-dependent death, but found that this effect was independent of PERK inactivation. Indeed, these two compounds turned out to be direct RIPK1 inhibitors, with comparable potency to the recently developed RIPK1 inhibitor GSK'963 (about 100 times more potent than NEC-1s). Importantly, these compounds completely inhibited TNF-mediated RIPK1-dependent cell death at a concentration that did not affect PERK activity in cells. In vivo, GSK2656157 administration protected mice from lethal doses of TNF independently of PERK inhibition and as efficiently as GSK'963. Together, our results not only report on new and very potent RIPK1 inhibitors but also highlight the risk of misinterpretation when using these two PERK inhibitors in the context of ER stress, cell death and inflammation.
Keywords
UNFOLDED PROTEIN RESPONSE, ENDOPLASMIC-RETICULUM STRESS, NF-KAPPA-B, KINASE INHIBITORS, CELL-DEATH, ER STRESS, TNF-ALPHA, INFLAMMATION, DISCOVERY, NECROPTOSIS

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Citation

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Chicago
Rojas Rivera, Diego, Tinneke Delvaeye, Ria Roelandt, Wim Nerinckx, Koen Augustyns, Peter Vandenabeele, and Mathieu Bertrand. 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 and Differentiation 24 (6): 1100–1110.
APA
Rojas Rivera, D., Delvaeye, T., Roelandt, R., Nerinckx, W., Augustyns, K., Vandenabeele, P., & Bertrand, M. (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 AND DIFFERENTIATION, 24(6), 1100–1110.
Vancouver
1.
Rojas Rivera D, Delvaeye T, Roelandt R, Nerinckx W, Augustyns K, Vandenabeele P, et al. When PERK inhibitors turn out to be new potent RIPK1 inhibitors : critical issues on the specificity and use of GSK2606414 and GSK2656157. CELL DEATH AND DIFFERENTIATION. 2017;24(6):1100–10.
MLA
Rojas Rivera, Diego, Tinneke Delvaeye, Ria Roelandt, et al. “When PERK Inhibitors Turn Out to Be New Potent RIPK1 Inhibitors : Critical Issues on the Specificity and Use of GSK2606414 and GSK2656157.” CELL DEATH AND DIFFERENTIATION 24.6 (2017): 1100–1110. Print.
@article{8524051,
  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 IRE1 alpha, 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 molecule inhibitors of IRE1 alpha and PERK have become attractive tools for the potential therapeutic manipulation of the UPR in inflammatory conditions. TNF is a master pro-inflammatory cytokine that drives inflammation either directly by promoting gene activation, or indirectly by inducing RIPK1 kinase-dependent cell death, in the form of apoptosis or necroptosis. To evaluate the potential contribution of the UPR to TNF-induced cell death, we tested the effects of two commonly used PERK inhibitors, GSK2606414 and GSK2656157. Surprisingly, we observed that both compounds completely repressed TNF-mediated RIPK1 kinase-dependent death, but found that this effect was independent of PERK inactivation. Indeed, these two compounds turned out to be direct RIPK1 inhibitors, with comparable potency to the recently developed RIPK1 inhibitor GSK'963 (about 100 times more potent than NEC-1s). Importantly, these compounds completely inhibited TNF-mediated RIPK1-dependent cell death at a concentration that did not affect PERK activity in cells. In vivo, GSK2656157 administration protected mice from lethal doses of TNF independently of PERK inhibition and as efficiently as GSK'963. Together, our results not only report on new and very potent RIPK1 inhibitors but also highlight the risk of misinterpretation when using these two PERK inhibitors in the context of ER stress, cell death and inflammation.},
  author       = {Rojas Rivera, Diego and Delvaeye, Tinneke and Roelandt, Ria and Nerinckx, Wim and Augustyns, Koen and Vandenabeele, Peter and Bertrand, Mathieu},
  issn         = {1350-9047},
  journal      = {CELL DEATH AND DIFFERENTIATION},
  keyword      = {UNFOLDED PROTEIN RESPONSE,ENDOPLASMIC-RETICULUM STRESS,NF-KAPPA-B,KINASE INHIBITORS,CELL-DEATH,ER STRESS,TNF-ALPHA,INFLAMMATION,DISCOVERY,NECROPTOSIS},
  language     = {eng},
  number       = {6},
  pages        = {1100--1110},
  title        = {When PERK inhibitors turn out to be new potent RIPK1 inhibitors : critical issues on the specificity and use of GSK2606414 and GSK2656157},
  url          = {http://dx.doi.org/10.1038/cdd.2017.58},
  volume       = {24},
  year         = {2017},
}

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