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Pharmacological targeting of the unfolded protein response for disease intervention

Nature Chemical Biology volume 15, pages 764–775 (2019)Cite this article

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A Publisher Correction to this article was published on 22 August 2019

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Abstract

Accumulation of unfolded proteins at the endoplasmic reticulum (ER) is a salient attribute of many human diseases including obesity, liver disorders, cancer, diabetes and neurodegeneration. To restore ER proteostasis, cells activate the unfolded protein response (UPR), a signaling pathway that imposes adaptive programs or triggers apoptosis of damaged cells. The UPR is critical to sustain the normal function of specialized secretory cells (i.e., pancreatic β cells and B lymphocytes) and to control the production of lipids and cholesterol in the liver. In the context of disease, adaptive UPR responses have been linked to the growth of solid tumors, whereas chronic ER stress contributes to cell dysfunction in brain diseases, metabolic syndromes, among other conditions. Here we discuss recent developments in the design and optimization of novel compounds to manipulate UPR signaling and their efficacy in various disease models.

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Fig. 1: Unfolded protein response pathways and interventions.
Fig. 2: Small molecules to target the ISR.
Fig. 3: Small molecules to target IRE1α.
Fig. 4: Small molecules to target PERK.
Fig. 5: Compounds that modulates ATF6.

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  • 22 August 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

References

  1. Karagöz, G. E., Acosta-Alvear, D. & Walter, P. The unfolded protein response: detecting and responding to fluctuations in the protein-folding capacity of the endoplasmic reticulum. Cold Spring Harb. Perspect. Biol. a033886 (2019).

  2. Wang, M. & Kaufman, R. J. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529, 326–335 (2016).

    CAS  PubMed  Google Scholar 

  3. Oakes, S. A. & Papa, F. R. The role of endoplasmic reticulum stress in human pathology. Annu. Rev. Pathol. 10, 173–194 (2015).

    CAS  PubMed  Google Scholar 

  4. Hetz, C. & Glimcher, L. H. Fine-tuning of the unfolded protein response: assembling the IRE1α interactome. Mol. Cell 35, 551–561 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374–1395 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hetz, C., Chevet, E. & Oakes, S. A. Proteostasis control by the unfolded protein response. Nat. Cell Biol. 17, 829–838 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Asada, R., Kanemoto, S., Kondo, S., Saito, A. & Imaizumi, K. The signalling from endoplasmic reticulum-resident bZIP transcription factors involved in diverse cellular physiology. J. Biochem. 149, 507–518 (2011).

    CAS  PubMed  Google Scholar 

  8. Lebeaupin, C. et al. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J. Hepatol. 69, 927–947 (2018).

    CAS  PubMed  Google Scholar 

  9. Cubillos-Ruiz, J. R., Bettigole, S. E. & Glimcher, L. H. Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer. Cell 168, 692–706 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Hetz, C. & Saxena, S. ER stress and the unfolded protein response in neurodegeneration. Nat. Rev. Neurol. 13, 477–491 (2017).

    CAS  PubMed  Google Scholar 

  11. Bettigole, S. E. & Glimcher, L. H. Endoplasmic reticulum stress in immunity. Annu. Rev. Immunol. 33, 107–138 (2015).

    CAS  PubMed  Google Scholar 

  12. Volkmann, K. et al. Potent and selective inhibitors of the inositol-requiring enzyme 1 endoribonuclease. J. Biol. Chem. 286, 12743–12755 (2011). This study reported one of the first selective and in vivo active IRE1α RNase inhibitors.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Cross, B. C. et al. The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc. Natl Acad. Sci. USA 109, E869–E878 (2012).

    CAS  PubMed  Google Scholar 

  14. Papandreou, I. et al. Identification of an Ire1α endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood 117, 1311–1314 (2011). This study reported one of the first selective and in vivo active IRE1α RNase inhibitors and its impact in cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Mimura, N. et al. Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma. Blood 119, 5772–5781 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sanches, M. et al. Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors. Nat. Commun. 5, 4202 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Tang, C. H. et al. Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival. J. Clin. Invest. 124, 2585–2598 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Ranatunga, S. et al. Synthesis of novel tricyclic chromenone-based inhibitors of IRE-1 RNase activity. J. Med. Chem. 57, 4289–4301 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhao, N. et al. Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer. J. Clin. Invest. 128, 1283–1299 (2018).

    PubMed  PubMed Central  Google Scholar 

  20. Logue, S. E. et al. Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy. Nat. Commun. 9, 3267 (2018).

    PubMed  PubMed Central  Google Scholar 

  21. Sato, H., Shiba, Y., Tsuchiya, Y., Saito, M. & Kohno, K. 4μ8C inhibits insulin secretion independent of IRE1α RNase activity. Cell Struct. Funct. 42, 61–70 (2017).

    CAS  PubMed  Google Scholar 

  22. Chan, S. M. H., Lowe, M. P., Bernard, A., Miller, A. A. & Herbert, T. P. The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4µ8C, is also a potent cellular antioxidant. Biochem. J. 475, 923–929 (2018).

    CAS  PubMed  Google Scholar 

  23. Wang, L. et al. Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors. Nat. Chem. Biol. 8, 982–989 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ghosh, R. et al. Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158, 534–548 (2014). This study reported the first allosteric inhibitors of IRE1α and its possible implications in the treatment of diabetes.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Harrington, P. E. et al. Unfolded protein response in cancer: IRE1α inhibition by selective kinase ligands does not impair tumor cell viability. ACS Med. Chem. Lett. 6, 68–72 (2014).

    PubMed  PubMed Central  Google Scholar 

  26. Feldman, H. C. et al. Structural and functional analysis of the allosteric inhibition of IRE1α with ATP-competitive ligands. ACS Chem. Biol. 11, 2195–2205 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Concha, N. O. et al. Long-range inhibitor-induced conformational regulation of human IRE1α endoribonuclease activity. Mol. Pharmacol. 88, 1011–1023 (2015).

    CAS  PubMed  Google Scholar 

  28. Waller, D. D. et al. A covalent cysteine-targeting kinase inhibitor of Ire1 permits allosteric control of endoribonuclease activity. ChemBioChem 17, 843–851 (2016).

    CAS  PubMed  Google Scholar 

  29. Axten, J. M. et al. 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, 7193–7207 (2012). This study reports the discovery of the first selective PERK inhibitor.

    CAS  PubMed  Google Scholar 

  30. Axten, J. M. et al. Discovery of GSK2656157: an optimized PERK inhibitor selected for preclinical development. ACS Med. Chem. Lett. 4, 964–968 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Rojas-Rivera, D. 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 Differ. 24, 1100–1110 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Smith, A. L. et al. Discovery of 1H-pyrazol-3(2H)-ones as potent and selective inhibitors of protein kinase R-like endoplasmic reticulum kinase (PERK). J. Med. Chem. 58, 1426–1441 (2015).

    CAS  PubMed  Google Scholar 

  33. Halliday, M. et al. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis. 6, e1672 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Boyce, M. et al. A selective inhibitor of eIF2α dephosphorylation protects cells from ER stress. Science 307, 935–939 (2005). This study reports the first successful screening to identify small molecules that improve ER proteostasis.

    CAS  PubMed  Google Scholar 

  35. Tsaytler, P., Harding, H. P., Ron, D. & Bertolotti, A. Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science 332, 91–94 (2011).

    CAS  PubMed  Google Scholar 

  36. Das, I. et al. Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science 348, 239–242 (2015). Identification of Sephin 1 as a selective inhibitor of the inducible eIF2α phosphatase and its application to treat neurodegenerative diseases.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Carrara, M., Sigurdardottir, A. & Bertolotti, A. Decoding the selectivity of eIF2α holophosphatases and PPP1R15A inhibitors. Nat. Struct. Mol. Biol. 24, 708–716 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Crespillo-Casado, A. et al. A Sephin1-insensitive tripartite holophosphatase dephosphorylates translation initiation factor 2α. J. Biol. Chem. 293, 7766–7776 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Crespillo-Casado, A., Chambers, J. E., Fischer, P. M., Marciniak, S. J. & Ron, D. PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz. eLife 6, e26109 (2017).

    PubMed  PubMed Central  Google Scholar 

  40. Sidrauski, C. et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife 2, e00498 (2013). This study reports the discovery of ISRIB as a selective inhibitor of ATF4 expression and its implications to brain function.

    PubMed  PubMed Central  Google Scholar 

  41. Sekine, Y. et al. Stress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound. Science 348, 1027–1030 (2015). This study reports co-identification of eIF2B as the target of ISRIB.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Sidrauski, C. et al. Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response. eLife 4, e07314 (2015). This study reports co-identification of eIF2B as the target of ISRIB.

    PubMed  PubMed Central  Google Scholar 

  43. Zyryanova, A. F. et al. Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science 359, 1533–1536 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Tsai, J. C. et al. Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule. Science 359, eaaq0939 (2018).

    PubMed  PubMed Central  Google Scholar 

  45. Rabouw, H. H. et al. Small molecule ISRIB suppresses the integrated stress response within a defined window of activation. Proc. Natl Acad. Sci. USA 116, 2097–2102 (2019).

    PubMed  Google Scholar 

  46. Hearn, B. R. et al. Structure-activity studies of bis-O-arylglycolamides: inhibitors of the integrated stress response. ChemMedChem 11, 870–880 (2016).

    CAS  PubMed  Google Scholar 

  47. Wong, Y. L. et al. eIF2B activator prevents neurological defects caused by a chronic integrated stress response. eLife 8, e42940 (2019).

    PubMed  PubMed Central  Google Scholar 

  48. Halliday, M. et al. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain 140, 1768–1783 (2017).

    PubMed  PubMed Central  Google Scholar 

  49. Gallagher, C. M. et al. Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch. eLife 5, e11878 (2016). This study reports the identification of the first ATF6 inhibitors.

    PubMed  PubMed Central  Google Scholar 

  50. Gallagher, C. M. & Walter, P. Ceapins inhibit ATF6α signaling by selectively preventing transport of ATF6α to the Golgi apparatus during ER stress. eLife 5, e11880 (2016).

    PubMed  PubMed Central  Google Scholar 

  51. Plate, L. et al. Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation. eLife 5, e15550 (2016).

    PubMed  PubMed Central  Google Scholar 

  52. Paxman, R. et al. Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins. eLife 7, e37168 (2018).

    PubMed  PubMed Central  Google Scholar 

  53. Blackwood, E. A. et al. Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis. Nat. Commun. 10, 187 (2019).

    PubMed  PubMed Central  Google Scholar 

  54. Urra, H., Dufey, E., Avril, T., Chevet, E. & Hetz, C. Endoplasmic reticulum stress and the hallmarks of cancer. Trends Cancer 2, 252–262 (2016).

    PubMed  Google Scholar 

  55. Song, M. et al. IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature 562, 423–428 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Kriss, C. L. et al. Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice. Blood 120, 1027–1038 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Xie, H. et al. IRE1α RNase-dependent lipid homeostasis promotes survival in Myc-transformed cancers. J. Clin. Invest. 128, 1300–1316 (2018).

    PubMed  PubMed Central  Google Scholar 

  58. Sheng, X. et al. IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. Nat. Commun. 10, 323 (2019).

    PubMed  PubMed Central  Google Scholar 

  59. Atkins, C. et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 73, 1993–2002 (2013).

    CAS  PubMed  Google Scholar 

  60. Hamamura, K. et al. Attenuation of malignant phenotypes of breast cancer cells through eIF2α-mediated downregulation of Rac1 signaling. Int. J. Oncol. 44, 1980–1988 (2014).

    CAS  PubMed  Google Scholar 

  61. Feng, Y. X. et al. Epithelial-to-mesenchymal transition activates PERK-eIF2α and sensitizes cells to endoplasmic reticulum stress. Cancer Discov. 4, 702–715 (2014).

    CAS  PubMed  Google Scholar 

  62. Falletta, P. et al. Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma. Genes Dev. 31, 18–33 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Martínez, G., Khatiwada, S., Costa-Mattioli, M. & Hetz, C. ER proteostasis control of neuronal physiology and synaptic function. Trends Neurosci. 41, 610–624 (2018).

    PubMed  Google Scholar 

  64. Way, S. W. et al. Pharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic. Nat. Commun. 6, 6532 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Vieira, F. G. et al. Guanabenz treatment accelerates disease in a mutant SOD1 mouse model of ALS. PLoS One 10, e0135570 (2015).

    PubMed  PubMed Central  Google Scholar 

  66. Wang, L., Popko, B., Tixier, E. & Roos, R. P. Guanabenz, which enhances the unfolded protein response, ameliorates mutant SOD1-induced amyotrophic lateral sclerosis. Neurobiol. Dis. 71, 317–324 (2014).

    CAS  PubMed  Google Scholar 

  67. Jiang, H. Q. et al. Guanabenz delays the onset of disease symptoms, extends lifespan, improves motor performance and attenuates motor neuron loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis. Neuroscience 277, 132–138 (2014).

    CAS  PubMed  Google Scholar 

  68. Moreno, J. A. et al. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci. Transl. Med. 5, 206ra138 (2013).

    PubMed  Google Scholar 

  69. Ounallah-Saad, H., Sharma, V., Edry, E. & Rosenblum, K. Genetic or pharmacological reduction of PERK enhances cortical-dependent taste learning. J. Neurosci. 34, 14624–14632 (2014).

    PubMed  PubMed Central  Google Scholar 

  70. Radford, H., Moreno, J. A., Verity, N., Halliday, M. & Mallucci, G. R. PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathol. 130, 633–642 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Mercado, G. et al. Targeting PERK signaling with the small molecule GSK2606414 prevents neurodegeneration in a model of Parkinson’s disease. Neurobiol. Dis. 112, 136–148 (2018).

    CAS  PubMed  Google Scholar 

  72. Grande, V. et al. PERK inhibition delays neurodegeneration and improves motor function in a mouse model of Marinesco-Sjögren syndrome. Hum. Mol. Genet. 27, 2477–2489 (2018).

    CAS  PubMed  Google Scholar 

  73. Sidrauski, C., McGeachy, A. M., Ingolia, N. T. & Walter, P. The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. eLife 4, e05033 (2015).

    PubMed Central  Google Scholar 

  74. Larhammar, M. et al. Dual leucine zipper kinase-dependent PERK activation contributes to neuronal degeneration following insult. eLife 6, e20725 (2017).

    PubMed  PubMed Central  Google Scholar 

  75. Briggs, D. I. et al. Role of endoplasmic reticulum stress in learning and memory impairment and alzheimer’s disease-like neuropathology in the PS19 and APPSwe mouse models of tauopathy and amyloidosis. eNeuro 4, ENEURO.0025–17.2017 (2017).

    PubMed  PubMed Central  Google Scholar 

  76. Johnson, E. C. & Kang, J. A small molecule targeting protein translation does not rescue spatial learning and memory deficits in the hAPP-J20 mouse model of Alzheimer’s disease. PeerJ 4, e2565 (2016).

    PubMed  PubMed Central  Google Scholar 

  77. Chou, A. et al. Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury. Proc. Natl Acad. Sci. USA 114, E6420–E6426 (2017).

    CAS  PubMed  Google Scholar 

  78. Kabir, Z. D. et al. Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α. Mol. Psychiatry 22, 1096–1109 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Batista, G., Johnson, J. L., Dominguez, E., Costa-Mattioli, M. & Pena, J. L. Translational control of auditory imprinting and structural plasticity by eIF2α. eLife 5, e17197 (2016).

    PubMed  PubMed Central  Google Scholar 

  80. Martínez, G. et al. Regulation of memory formation by the transcription factor XBP1. Cell Rep. 14, 1382–1394 (2016).

    PubMed  Google Scholar 

  81. Koh, J. H., Wang, L., Beaudoin-Chabot, C. & Thibault, G. Lipid bilayer stress-activated IRE-1 modulates autophagy during endoplasmic reticulum stress. J. Cell Sci. 131, jcs21799 (2018).

    Google Scholar 

  82. Tam, A. B. et al. The UPR activator ATF6 responds to proteotoxic and lipotoxic stress by distinct mechanisms. Dev. Cell 46, 327–343.e7 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Kim, M. J. et al. Attenuation of PERK enhances glucose-stimulated insulin secretion in islets. J. Endocrinol. 236, 125–136 (2018).

    CAS  PubMed  Google Scholar 

  84. Mendez, A. S. et al. Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimic. eLife 4, e05434 (2015).

    PubMed Central  Google Scholar 

  85. Morita, S. et al. Targeting ABL-IRE1α signaling spares ER-stressed pancreatic β cells to reverse autoimmune diabetes. Cell Metab. 25, 883–897.e8 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Guan, B. J. et al. A unique ISR program determines cellular responses to chronic stress. Mol. Cell 68, 885–900 e886 (2017). This study reports the identification of an eIF2B-independent translation mechanism during chronic stress.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Chang, T. K. et al. Coordination between two branches of the unfolded protein response determines apoptotic cell fate. Mol. Cell 71, 629–636.e5 (2018).

    CAS  PubMed  Google Scholar 

  88. Smith, J. A. Regulation of cytokine production by the unfolded protein response; implications for infection and autoimmunity. Front. Immunol. 9, 422 (2018).

    PubMed  PubMed Central  Google Scholar 

  89. Dufey, E., Sepúlveda, D., Rojas-Rivera, D. & Hetz, C. Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 1. An overview. Am. J. Physiol. Cell Physiol. 307, C582–C594 (2014).

    CAS  PubMed  Google Scholar 

  90. Valenzuela, V., Jackson, K. L., Sardi, S. P. & Hetz, C. Gene Therapy Strategies to Restore ER proteostasis in disease. Mol. Ther. 26, 1404–1413 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Hetz, C., Chevet, E. & Harding, H. P. Targeting the unfolded protein response in disease. Nat. Rev. Drug Discov. 12, 703–719 (2013).

    CAS  PubMed  Google Scholar 

  92. Abdulkarim, B. et al. Guanabenz sensitizes pancreatic β cells to lipotoxic endoplasmic reticulum stress and apoptosis. Endocrinology 158, 1659–1670 (2017).

    PubMed  Google Scholar 

  93. Colla, E. et al. Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo. J. Neurosci. 32, 3306–3320 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Moreno, J. A. et al. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature 485, 507–511 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Rubovitch, V. et al. The neuroprotective effect of salubrinal in a mouse model of traumatic brain injury. Neuromolecular Med. 17, 58–70 (2015).

    CAS  PubMed  Google Scholar 

  96. Ohri, S. S., Hetman, M. & Whittemore, S. R. Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury. Neurobiol. Dis. 58, 29–37 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Nguyen, H. G. et al. Development of a stress response therapy targeting aggressive prostate cancer. Sci. Transl. Med. 10, eaar2036 (2018).

    PubMed  PubMed Central  Google Scholar 

  98. Palam, L. R., Gore, J., Craven, K. E., Wilson, J. L. & Korc, M. Integrated stress response is critical for gemcitabine resistance in pancreatic ductal adenocarcinoma. Cell Death Dis. 6, e1913 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Ming, J. et al. A novel chemical, STF-083010, reverses tamoxifen-related drug resistance in breast cancer by inhibiting IRE1/XBP1. Oncotarget 6, 40692–40703 (2015).

    PubMed  PubMed Central  Google Scholar 

  100. Thamsen, M. et al. Small molecule inhibition of IRE1α kinase/RNase has anti-fibrotic effects in the lung. PLoS One 14, e0209824 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank H. Urra for initial figure design. This work was directly funded by FONDAP program 15150012, Millennium Institute P09-015-F, CONICYT-Brazil 441921/2016-7, FONDEF ID16I10223, FONDEF D11E1007 and FONDECYT 1180186 (CH). In addition, we thank the support from the US Air Force Office of Scientific Research FA9550-16-1-0384, and Muscular Dystrophy Association, US Office of Naval Research-Global (ONR-G) N62909-16-1-2003 (C.H.).

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Authors and Affiliations

  1. Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile

    Claudio Hetz

  2. FONDAP Center for Geroscience, Brain Health and Metabolism, Santiago, Chile

    Claudio Hetz

  3. Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile

    Claudio Hetz

  4. Buck Institute for Research on Aging, Novato, CA, USA

    Claudio Hetz

  5. Department of Immunology and Infectious diseases, Harvard School of Public Health, Boston, MA, USA

    Claudio Hetz

  6. Medicinal Chemistry, Medicine Design, GlaxoSmithKline, Collegeville, PA, USA

    Jeffrey M. Axten

  7. Orinove Inc., Newbury Park, CA, USA

    John B. Patterson

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Correspondence to Claudio Hetz, Jeffrey M. Axten or John B. Patterson.

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J.M.A. is an employee and stockholder of GlaxoSmithKline, and a named inventor of PERK inhibitor patents owned by GlaxoSmithKline. J.B.P. is and employee and stockholder of Orinove, Inc. and a named inventor of IRE1 inhibitor patents owned by Orinove, Inc.

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Hetz, C., Axten, J.M. & Patterson, J.B. Pharmacological targeting of the unfolded protein response for disease intervention. Nat Chem Biol 15, 764–775 (2019). https://doi.org/10.1038/s41589-019-0326-2

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