Discovery of toxoflavin,a potent IRE1α inhibitor acting through structure-dependent oxidative inhibition
文献类型：期刊论文
| 作者 | Liu Changmei4; Nie Litong4; Jiang Haini3; Xu Lei3; Zhang Kunzhi4; Fan Lixia4; Gao Anhui4; Lin Luling2; Wang Xiangyu1; Tan Mingjia4 |
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2023 |
| 卷号 | 44期号:1页码:234 |
| ISSN号 | 1671-4083 |
| 关键词 | endoplasmic reticulum stress toxoflavin reactive oxygen species IRE1α XBP1 |
| 英文摘要 | Inositol-requiring enzyme 1α (IRE1α) is the most conserved endoplasmic reticulum (ER) stress sensor with two catalytic domains,kinase and RNase,in its cytosolic portion.IRE1α inhibitors have been used to improve existing clinical treatments against various cancers.In this study we identified toxoflavin (TXF) as a new-type potent small molecule IRE1α inhibitor.We used luciferase reporter systems to screen compounds that inhibited the IRE1α-XBP1s signaling pathway.As a result,TXF was found to be the most potent IRE1α RNase inhibitor with an IC_(50) value of 0.226 μM.Its inhibitory potencies on IRE1α kinase and RNase were confirmed in a series of cellular and in vitro biochemical assays.Kinetic analysis showed that TXF caused time- and reducing reagent-dependent irreversible inhibition on IRE1α,implying that ROS might participate in the inhibition process.ROS scavengers decreased the inhibition of IRE1α by TXF,confirming that ROS mediated the inhibition process.Mass spectrometry analysis revealed that the thiol groups of four conserved cysteine residues (CYS-605,CYS-630,CYS-715 and CYS-951) in IRE1α were oxidized to sulfonic groups by ROS.In molecular docking experiments we affirmed the binding of TXF with IRE1α,and predicted its binding site,suggesting that the structure of TXF itself participates in the inhibition of IRE1α.Interestingly,CYS-951 was just near the docked site.In addition,the RNase IC_(50) and ROS production in vitro induced by TXF and its derivatives were negative correlated (r= -0.872).In conclusion,this study discovers a new type of IRE1α inhibitor that targets a predicted new alternative site located in the junction between RNase domain and kinase domain,and oxidizes conserved cysteine residues of IRE1α active sites to inhibit IRE1α.TXF could be used as a small molecule tool to study IRE1α's role in ER stress. |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/304812]  |
| 专题 | 新药研究国家重点实验室 |
| 作者单位 | 1.The First Affiliated Hospital,Jinan University 2.Institute of Biomedical Engineering,The Second Clinical Medical College,Jinan University 3.Zhongshan Institute for Drug Discovery,Shanghai Institute of Materia Medica,Chinese Academy of Sciences 4.中国科学院上海药物研究所 |
| 推荐引用方式 GB/T 7714 | Liu Changmei,Nie Litong,Jiang Haini,et al. Discovery of toxoflavin,a potent IRE1α inhibitor acting through structure-dependent oxidative inhibition[J]. ACTA PHARMACOLOGICA SINICA,2023,44(1):234. |
| APA | Liu Changmei.,Nie Litong.,Jiang Haini.,Xu Lei.,Zhang Kunzhi.,...&Jiang Kailong.(2023).Discovery of toxoflavin,a potent IRE1α inhibitor acting through structure-dependent oxidative inhibition.ACTA PHARMACOLOGICA SINICA,44(1),234. |
| MLA | Liu Changmei,et al."Discovery of toxoflavin,a potent IRE1α inhibitor acting through structure-dependent oxidative inhibition".ACTA PHARMACOLOGICA SINICA 44.1(2023):234. |
入库方式： OAI收割
来源：上海药物研究所
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