安普克
化学
AMP活化蛋白激酶
激活剂(遗传学)
癌症研究
细胞生长
蛋白激酶A
结直肠癌
下调和上调
激酶
氧化磷酸化
细胞生物学
生物化学
癌症
内科学
生物
医学
受体
基因
作者
Yao-Hao Xu,Yu-Tao Hu,Shumin Xu,Bingbing Song,Hao Yuan,Dandan Zhao,Shi-Yao Guo,Zhi Jiang,Liyuan Wei,Yong Rao,Jia‐Heng Tan,Shi‐Liang Huang,Qingjiang Li,Shuo-Bin Chen,Shuo-Bin Chen
标识
DOI:10.1021/acs.jmedchem.3c00085
摘要
Metabolic reprogramming is a crucial hallmark of tumorigenesis. Modulating the reprogrammed energy metabolism is an attractive anticancer therapeutic strategy. We previously found a natural product, bouchardatine, modulated aerobic metabolism and inhibited proliferation in the colorectal cancer cell (CRC). Herein, we designed and synthesized a new series of bouchardatine derivatives to discover more potential modulators. We applied the dual-parametric high-content screening (HCS) to evaluate their AMP-activated protein kinase (AMPK) modulation and CRC proliferation inhibition effect simultaneously. And we found their antiproliferation activities were highly correlated to AMPK activation. Among them, 18a was identified with nanomole-level antiproliferation activities against several CRCs. Interestingly, the evaluation found that 18a selectively upregulated oxidative phosphorylation (OXPHOS) and inhibited proliferation by modulating energy metabolism. Additionally, this compound effectively inhibited the RKO xenograft growth along with AMPK activation. In conclusion, our study identified 18a as a promising candidate for CRC treatment and suggested a novel anti-CRC strategy by AMPK activating and OXPHOS upregulating.
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