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.

中文翻译：

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IRE1 活性调节的结构和分子基础

未折叠蛋白反应是一种适应性途径，由内质网 (ER) 稳态改变触发。它由三个主要的内质网应激传感器转导，其中肌醇需要酶 1 (IRE1) 是进化上最保守的。IRE1 是一种内质网驻留 I 型跨膜蛋白，具有 ER 腔结构域，可感知蛋白质折叠状态以及催化激酶和 RNase 胞质结构域。近年来，IRE1 已成为各种疾病的相关治疗靶点，包括退行性、炎症和代谢病理以及癌症。因此，开发了几种改变 IRE1 活性的药物，它们靶向催化活性并在临床前病理小鼠模型中显示出一些功效。在这次审查中，我们从结构的角度描述了针对 IRE1 活性的不同药物及其作用模式，从而确定了常见和不同的作用模式。基于这些信息，我们讨论了如何开发新的 IRE1 靶向药物以超越当前可用的分子。