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
  • 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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