蛋白质亚单位
化学
ATP合酶
小分子
缺氧诱导因子1
生物化学
缺氧诱导因子
翻译(生物学)
信使核糖核酸
生物
细胞生物学
分子生物学
酶
基因
转录因子
作者
Huiti Li,Yali Liu,Zian Xue,Li Zhang,Xiaoxue Ruan,Jintong Yang,Zhongjiao Fan,Huabin Zhao,Yu Cao,Guoqiang Chen,Ying Xu,Lu Zhou
标识
DOI:10.1002/advs.202301071
摘要
Hypoxia inducible factor-1α (HIF-1α) plays a critical role in cellular adaptation to hypoxia and it is a potential therapeutic target for anti-cancer drugs. Applying high-throughput screening, here it is found that HI-101, a small molecule containing an adamantaniline moiety, effectively reduces HIF-1α protein expression. With the compound as a hit, a probe (HI-102) is developed for target identification by affinity-based protein profiling. The catalytic β subunit of mitochondrial FO F1 -ATP synthase, ATP5B, is identified as the binding protein of HI-derivatives. Mechanistically, HI-101 promotes the binding of HIF-1α mRNA to ATP5B, thus inhibiting HIF-1α translation and the following transcriptional activity. Further modifications of HI-101 lead to HI-104, a compound with good pharmacokinetic properties, exhibiting antitumor activity in MHCC97-L mice xenograft model, and HI-105, the most potent compound with an IC50 of 26 nm. The findings provide a new strategy for further developing HIF-1α inhibitors by translational inhibition through ATP5B.
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