Cambridge Institute for Medical Research, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
Nat Rev Drug Discov. 2022 Feb;21(2):115-140. doi: 10.1038/s41573-021-00320-3. Epub 2021 Oct 26.
The accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress, resulting in activation of the unfolded protein response (UPR) that aims to restore protein homeostasis. However, the UPR also plays an important pathological role in many diseases, including metabolic disorders, cancer and neurological disorders. Over the last decade, significant effort has been invested in targeting signalling proteins involved in the UPR and an array of drug-like molecules is now available. However, these molecules have limitations, the understanding of which is crucial for their development into therapies. Here, we critically review the existing ER stress and UPR-directed drug-like molecules, highlighting both their value and their limitations.
内质网（ER）中错误折叠蛋白质的积累会导致内质网应激，从而激活旨在恢复蛋白质平衡的未折叠蛋白反应（UPR）。然而，UPR 在许多疾病中也起着重要的病理作用，包括代谢紊乱、癌症和神经紊乱。在过去的十年中，人们投入了大量的精力来针对 UPR 涉及的信号蛋白，现在已经有了一系列类似药物的分子。然而，这些分子存在局限性，了解这些局限性对于将它们开发成治疗方法至关重要。在这里，我们批判性地回顾了现有的 ER 应激和 UPR 导向的类似药物的分子，强调了它们的价值和局限性。
