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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Crotonates / chemical synthesis
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Crotonates / chemistry*
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Crotonates / pharmacology*
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Dihydroorotate Dehydrogenase / antagonists & inhibitors*
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Drug Design*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Humans
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Hydroxybutyrates / chemical synthesis
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Hydroxybutyrates / chemistry*
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Hydroxybutyrates / pharmacology*
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Neoplasms / drug therapy*
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Neoplasms / pathology
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Nitriles / chemical synthesis
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Nitriles / chemistry*
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Nitriles / pharmacology*
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Structure-Activity Relationship
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Toluidines / chemical synthesis
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Toluidines / chemistry*
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Toluidines / pharmacology*
Substances
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Antineoplastic Agents
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Crotonates
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Dihydroorotate Dehydrogenase
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Enzyme Inhibitors
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Hydroxybutyrates
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Nitriles
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Toluidines
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teriflunomide