ATF4
赫拉
IC50型
化学
信号转导
药理学
细胞生物学
分子生物学
生物化学
生物
体外
细胞凋亡
未折叠蛋白反应
作者
Yifeng Pei,S. M. Liu,Lixun Wang,Chao Chen,Mengqiu Hu,Xue Yang,Dezhong Guan,Lingfeng Xie,Liang Hong,Jinpei Zhou,Huibin Zhang
标识
DOI:10.1002/cmdc.202300716
摘要
The eukaryotic initiation factor 2B (eIF2B) is a key regulator in protein-regulated signaling pathways and is closely related to the function of the central nervous system. Modulating eIF2B could retard the process of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and vanishing white matter disease (VWM) et al. Here, we designed and synthesized a series of novel eIF2B activators containing oxadiazole fragments. The activating effects of compounds on eIF2B were investigated through testing the inhibition of ATF4 expression. Of all the targeted compounds, compounds 21 and 29 exhibited potent inhibition on ATF4 expression with IC50 values of 32.43 nM and 47.71 nM, respectively, which were stronger than that of ISRIB (IC50=67.90 nM). ATF4 mRNA assay showed that these two compounds could restore ATF4 mRNA to normal levels in thapsigargin-stimulated HeLa cells. Protein Translation assay showed that both compounds were effective in restoring protein synthesis. Compound potency assay showed that both compounds had similar potency to ISRIB with EC50 values of 5.844 and 37.70 nM. Cytotoxicity assay revealed that compounds 21 and 29 had low toxicity and were worth further investigation.
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