二氢月桂酸脱氢酶
特瑞氟米特
化学
嘧啶代谢
药理学
IC50型
嘧啶
化学图书馆
酶
生物化学
体外
医学
多发性硬化
免疫学
小分子
嘌呤
芬戈莫德
作者
Chungen Li,Yue Zhou,Jing Xu,Xia Zhou,Zongkai Huang,Ting Zeng,Xiaowei Yang,Lei Tao,Kun Gou,Xi Zhong,Qiang Chen,Youfu Luo,Yinglan Zhao
标识
DOI:10.1016/j.ejmech.2022.114489
摘要
Human dihydroorotate dehydrogenase (hDHODH) is a key enzyme in the de novo synthesis pathway of pyrimidine nucleotide in cells. The moderate efficiency of teriflunomide, an approved hDHODH inhibitor for the treatment of multiple sclerosis, limited its therapeutic application of malignancy. Herein, thirty-seven novel teriflunomide derivatives with a biphenyl scaffold were designed, synthesized and evaluated. As a result, the optimal compound A37 exhibited a potent hDHODH inhibitory activity with an IC50 value of 10.2 nM, which was about 40-fold stronger than that of teriflunomide (IC50 = 407.8 nM), and showed favorable antiproliferative activities against HCT116 cells with an IC50 value of 0.3 μM. Meanwhile, A37 displayed an acceptable safety profile at an oral dosage of 400 mg/kg in the acute toxicity assay, and exhibited a promising antitumor effect with tumor growth inhibition rate of 54.4% at an oral dosage of 30 mg/kg in HCT116 xenograft model. These results indicate that A37 is an efficacious hDHODH inhibitor with potential in the treatment of colorectal carcinoma.
科研通智能强力驱动
Strongly Powered by AbleSci AI