三阴性乳腺癌
二氢月桂酸脱氢酶
化学
癌症研究
细胞生长
生长抑制
药理学
毒性
酶
细胞培养
乳腺癌
生物化学
癌症
生物
内科学
医学
有机化学
遗传学
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
标识
DOI:10.1021/acs.jmedchem.1c01402
摘要
Human dihydroorotate dehydrogenase (hDHODH) is an attractive tumor target essential to de novo pyrimidine biosynthesis. Novel potent hDHODH 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 hDHODH and triple-negative breast cancer (TNBC) cell lines, MDA-MB-231/-468. Interestingly, we found that hDHODH is required for proliferation and survival of TNBC cells, and several ASCs significantly inhibited TNBC cell growth and induced their apoptosis via hDHODH inhibition. Furthermore, the novel and potent hDHODH 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 hDHODH inhibitor for further development of potent anticancer agents and a potential therapeutic strategy for TNBC.
科研通智能强力驱动
Strongly Powered by AbleSci AI