GPX4
化学
HT1080型
自噬
活性氧
脂质过氧化
癌细胞
溶酶体
生物化学
细胞生物学
程序性细胞死亡
谷胱甘肽过氧化物酶
谷胱甘肽
氧化应激
细胞
癌症
酶
生物
细胞凋亡
遗传学
作者
Xiaomei Li,Mengdie Hu,Yanping Zhang,Hui Hua,Yujie Sun,Qiuping Xiang,Dongsheng Zhu
标识
DOI:10.1016/j.bioorg.2024.107115
摘要
Ferroptosis is an iron-dependent form of oxidative cell death induced by lipid peroxidation accumulation. Glutathione peroxidase 4 (GPX4) plays a key role in the regulation of ferroptosis and is considered to be a promising therapeutic target for cancer and other human diseases. Herein, we describe our design, synthesis, and biological evaluation of a series of HyT-based degraders of the GPX4. One of the most promising compounds, 7b (ZX782), effectively induces dose- and time-dependent degradation of GPX4 protein and potently suppresses the growth of human fibrosarcoma HT1080 cells, which are highly sensitive to ferroptosis and widely used for evaluating compound specificity in ferroptosis. Mechanism investigation indicated that 7b depletes GPX4 through both the ubiquitin–proteasome and the autophagy-lysosome. Furthermore, the degradation of GPX4 induced by 7b could significantly increase the accumulation of lipid reactive oxygen species (ROS) in HT1080 cells, ultimately leading to ferroptosis. Overall, compound 7b exhibits robust potency in depleting endogenous GPX4, thereby modulating ferroptosis in cancer cells.
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