Proteostasis and Cancer Team, INSERM U1242, COSS Laboratory, Université de Rennes, Rennes, France; Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France.
Institut des Science Chimiques de Rennes, CNRS UMR6226, Université de Rennes, Rennes, France.
Trends Cancer. 2020 Dec;6(12):1018-1030. doi: 10.1016/j.trecan.2020.07.006. Epub 2020 Aug 26.
IRE1α (inositol requiring enzyme 1 alpha) is one of the main transducers of the unfolded protein response (UPR). IRE1α plays instrumental protumoral roles in several cancers, and high IRE1α activity has been associated with poorer prognoses. In this context, IRE1α has been identified as a potentially relevant therapeutic target. Pharmacological inhibition of IRE1α activity can be achieved by targeting either the kinase domain or the RNase domain. Herein, the recent advances in IRE1α pharmacological targeting is summarized. We describe the identification and optimization of IRE1α inhibitors as well as their mode of action and limitations as anticancer drugs. The potential pitfalls and challenges that could be faced in the clinic, and the opportunities that IRE1α modulating strategies may present are discussed.
IRE1α（肌醇需求酶 1α）是未折叠蛋白反应（UPR）的主要转导子之一。IRE1α 在几种癌症中起着重要的促肿瘤作用，高 IRE1α 活性与预后较差相关。在这种情况下，IRE1α 已被确定为一个潜在的相关治疗靶点。IRE1α 活性的药理学抑制可以通过靶向激酶结构域或核糖核酸酶结构域来实现。本文总结了 IRE1α 的药理学靶向的最新进展。我们描述了 IRE1α 抑制剂的鉴定和优化，以及它们作为抗癌药物的作用模式和局限性。讨论了在临床中可能面临的潜在陷阱和挑战，以及 IRE1α 调节策略可能带来的机会。
