The Unfolded Protein response is an adaptive pathway triggered upon alteration of endoplasmic reticulum (ER) homeostasis. It is transduced by three major ER stress sensors, among which the Inositol Requiring Enzyme 1 (IRE1) is the most evolutionarily conserved. IRE1 is an ER-resident type I transmembrane protein exhibiting an ER luminal domain that senses the protein folding status and a catalytic kinase and RNase cytosolic domain. In recent years, IRE1 has emerged as a relevant therapeutic target in various diseases including degenerative, inflammatory and metabolic pathologies and cancer. As such several drugs altering IRE1 activity were developed that target either catalytic activity and showed some efficacy in preclinical pathological mouse models. In this review, we describe the different drugs identified to target IRE1 activity as well as their mode of action from a structural perspective, thereby identifying common and different modes of action. Based on this information we discuss on how new IRE1-targeting drugs could be developed that outperform the currently available molecules.
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August 2021
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Cover Image
Cover Image
The image on the cover of this issue of Biochemical Journal (volume 478, issue 15) shows the crystal structure of the type III kinase inhibitor GSK2850163 bound to IRE1 kinase site, with key structural elements of kinases highlighted. Image courtesy of Langlais et al. (pages 2953–2975).
Review Article|
August 10 2021
Structural and molecular bases to IRE1 activity modulation
Timothy Langlais;
Timothy Langlais
1Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) UMR 6226, Rennes 35042, France
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Diana Pelizzari-Raymundo
;
Diana Pelizzari-Raymundo
2Proteostasis & Cancer Team INSERM U1242 « Chemistry, Oncogenesis Stress Signaling », Université de Rennes, Rennes, France
3Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
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Sayyed Jalil Mahdizadeh
;
Sayyed Jalil Mahdizadeh
4Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden
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Nicolas Gouault
;
Nicolas Gouault
1Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) UMR 6226, Rennes 35042, France
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Francois Carreaux
;
Francois Carreaux
1Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) UMR 6226, Rennes 35042, France
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Eric Chevet
;
Eric Chevet
2Proteostasis & Cancer Team INSERM U1242 « Chemistry, Oncogenesis Stress Signaling », Université de Rennes, Rennes, France
3Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
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Leif A. Eriksson
;
Leif A. Eriksson
4Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden
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Xavier Guillory
1Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) UMR 6226, Rennes 35042, France
2Proteostasis & Cancer Team INSERM U1242 « Chemistry, Oncogenesis Stress Signaling », Université de Rennes, Rennes, France
3Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
Correspondence: Xavier Guillory (xavier.guillory@univ-rennes1.fr)
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Publisher: Portland Press Ltd
Received:
May 18 2021
Revision Received:
July 06 2021
Accepted:
July 12 2021
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2021
Biochem J (2021) 478 (15): 2953–2975.
Article history
Received:
May 18 2021
Revision Received:
July 06 2021
Accepted:
July 12 2021
Citation
Timothy Langlais, Diana Pelizzari-Raymundo, Sayyed Jalil Mahdizadeh, Nicolas Gouault, Francois Carreaux, Eric Chevet, Leif A. Eriksson, Xavier Guillory; Structural and molecular bases to IRE1 activity modulation. Biochem J 13 August 2021; 478 (15): 2953–2975. doi: https://doi.org/10.1042/BCJ20200919
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