Target fishing and mechanistic insights of the natural anticancer drug candidate chlorogenic acid  

作　　者：Qinghua Wang Tingting Du Zhihui Zhang Qingyang Zhang Jie Zhang Wenbin Li Jian-Dong Jiang Xiaoguang Chen Hai-Yu Hu 

机构地区：[1]State Key Laboratory of Bioactive Substances and Function of Natural Medicine,Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation,Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China [2]Sichuan Jiuzhang Biological Science and Technology Co.,Ltd.,Chengdu 610041,China [3]Cancer Center,Beijing Tiantan Hospital,Capital Medical University,Beijing 100070,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第10期4431-4442,共12页药学学报（英文版）

基　　金：supported and inspired by the National Natural Science Foundation of China(NSFC)projects(22122705,22077139,82293684);CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-054,2022-12M-1-014,China).

摘　　要：Chlorogenic acid(CGA)is a natural product that effectively inhibits tumor growth,demonstrated in many preclinical models,and phase II clinical trials for patients with glioma.However,its direct proteomic targets and anticancer molecular mechanisms remain unknown.Herein,we developed a novel bi-functional photo-affinity probe PAL/CGA and discovered mitochondrial acetyl-CoA acetyltransferase 1(ACAT1)was one of the main target proteins of CGA by using affinity-based protein profiling(AfBPP)chemical proteomic approach.We performed in-depth studies on ACAT1/CGA interactions via multiple assays including SPR,ITC,and cryo-EM.Importantly,we demonstrated that CGA impaired cancer cell proliferation by inhibiting the phosphorylation of tetrameric ACAT1 on Y407 residue through a novel mode of action in vitro and in vivo.Our study highlights the use of AfBPP platforms in uncovering unique druggable modalities accessed by natural products.And identifying the molecular target of CGA sheds light on the future clinical application of CGA for cancer therapy.

关 键 词：AfBPP Natural product Chlorogenic acid PROBE ACAT1 

分 类 号：R979.1[医药卫生—药品]