Exploring Marine-Derived Ascochlorins as Novel Human Dihydroorotate Dehydrogenase Inhibitors for Treatment of Triple-Negative Breast Cancer

作者：Xiaowei Luo, Guodi Cai, Yinfeng Guo, Chenghai Gao, Wei-Feng Huang, Zhenhua Zhang, Humu Lu, Kai Liu, Jianghe Chen, Xiao‐Feng Xiong, Jinping Lei, Xuefeng Zhou, Junjian Wang, Yonghong Liu · 发表于：Journal of Medicinal Chemistry · 年份：2021 · DOI：10.1021/acs.jmedchem.1c01402 · 被引用次数：54 · 研究领域：Biochemical and Molecular Research、Cancer, Hypoxia, and Metabolism、RNA modifications and cancer

Human dihydroorotate dehydrogenase ( h DHODH) is an attractive tumor target essential to de novo pyrimidine biosynthesis. Novel potent h DHODH inhibitors with low toxicity are urgently needed. Herein, we demonstrate the isolation of 25 ascochlorin (ASC) derivatives, including 13 new ones, from the coral-derived fungus Acremonium sclerotigenum, and several of them showed pronounced inhibitions against h DHODH and triple-negative breast cancer (TNBC) cell lines, MDA-MB-231/-468. Interestingly, we found that h DHODH is required for proliferation and survival of TNBC cells, and several ASCs significantly inhibited TNBC cell growth and induced their apoptosis via h DHODH inhibition. Furthermore, the novel and potent h DHODH inhibitors ( 1 and 21 ) efficiently suppressed tumor growth in patient-derived TNBC xenograft models without obvious body weight loss or overt toxicity in mice. Collectively, our findings offered a novel lead scaffold as the h DHODH inhibitor for further development of potent anticancer agents and a potential therapeutic strategy for TNBC.