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Pharmacological targeting of the unfolded protein response for disease intervention

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

This article has been updated

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.

Change history

  • 22 August 2019

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

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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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Correspondence to Claudio Hetz or 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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