2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of a Novel Series of Teriflunomide Derivatives as Potent Human Dihydroorotate Dehydrogenase Inhibitors for Malignancy Treatment

Design, Synthesis, and Biological Evaluation of a Novel Series of Teriflunomide Derivatives as Potent Human Dihydroorotate Dehydrogenase Inhibitors for Malignancy Treatment

  • J Med Chem. 2021 Dec 23;64(24):18175-18192. doi: 10.1021/acs.jmedchem.1c01711.
Chungen Li 1,  Xiaowei Yang 2,  Yuan Luo 1,  Huan Liu 2,  Xi Zhong 2,  Xia Zhou 1,  Ting Zeng 1,  Lei Tao 1,  Yue Zhou 1,  Kun Gou 1,  Xinyu Yang 1,  Xiaocong Liu 1,  Qiang Chen 1,  Yinglan Zhao 1 2,  Youfu Luo 1
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.
PMID: 34905371 DOI: 10.1021/acs.jmedchem.1c01711
Abstract

Human Dihydroorotate Dehydrogenase (hDHODH), as the fourth and rate-limiting Enzyme of the de novo pyrimidine synthesis pathway, is regarded as an attractive target for malignancy therapy. In the present study, a novel series of teriflunomide derivatives were designed, synthesized, and evaluated as hDHODH inhibitors. 13t was the optimal compound with promising enzymatic activity (IC50 = 16.0 nM), potent antiproliferative activity against human lymphoma Raji cells (IC50 = 7.7 nM), and excellent aqueous solubility (20.1 mg/mL). Mechanistically, 13t directly inhibited hDHODH and induced cell cycle S-phase arrest in Raji cells. The acute toxicity assay indicated a favorable safety profile of 13t. Notably, 13t displayed significant tumor growth inhibition activity with a tumor growth inhibition (TGI) rate of 81.4% at 30 mg/kg in a Raji xenograft model. Together, 13t is a promising inhibitor of hDHODH and a preclinical candidate for antitumor therapy, especially for lymphoma.

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