1. Academic Validation
  2. A novel series of teriflunomide derivatives as orally active inhibitors of human dihydroorotate dehydrogenase for the treatment of colorectal carcinoma

A novel series of teriflunomide derivatives as orally active inhibitors of human dihydroorotate dehydrogenase for the treatment of colorectal carcinoma

  • Eur J Med Chem. 2022 Aug 5:238:114489. doi: 10.1016/j.ejmech.2022.114489.
Chungen Li 1 Yue Zhou 1 Jing Xu 1 Xia Zhou 1 Zongkai Huang 1 Ting Zeng 1 Xiaowei Yang 2 Lei Tao 1 Kun Gou 1 Xi Zhong 2 Qiang Chen 1 Youfu Luo 3 Yinglan Zhao 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
  • 2 Department of Pharmacology, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
  • 3 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China. Electronic address: luo_youfu@scu.edu.cn.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China; Department of Pharmacology, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: zhaoyinglan@scu.edu.cn.
Abstract

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.

Keywords

Colorectal carcinoma; Teriflunomide derivatives; hDHODH inhibitor.

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