Abstract
Human thymidylate synthase (hTS) was targeted through a virtual screening approach. The most optimal inhibitor identified, 2-{4-hydroxy-2-[(2-hydroxybenzylidene)hydrazono]-2,5-dihydrothiazol-5-yl}-N-(3-trifluoromethylphenyl)acetamide (5), showed a mixed-type inhibition pattern, with a K(i) of 1.3 μM and activity against ovarian cancer cell lines with the same potency as cisplatin. X-ray studies revealed that it binds the inactive enzyme conformation. This study is the first example of a nonpeptidic inhibitor that binds the inactive hTS and exhibits anticancer activity against ovarian cancer cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acetanilides / chemical synthesis
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Acetanilides / pharmacology*
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Antineoplastic Agents / pharmacology
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Cisplatin / pharmacology
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Crystallography, X-Ray
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Drug Screening Assays, Antitumor
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Female
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High-Throughput Screening Assays*
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Humans
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Models, Molecular
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Molecular Structure
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / enzymology
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Ovarian Neoplasms / pathology
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Structure-Activity Relationship
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Thiazoles / chemical synthesis
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Thiazoles / chemistry*
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Thiazoles / pharmacology
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Thymidylate Synthase / antagonists & inhibitors*
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Thymidylate Synthase / metabolism
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Tumor Cells, Cultured
Substances
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2-(4-hydroxy-2-((2-hydroxybenzylidene)hydrazono)-2,5-dihydrothiazol-5-yl)-N-(3-trifluoromethylphenyl)acetamide
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Acetanilides
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Antineoplastic Agents
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Thiazoles
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Thymidylate Synthase
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Cisplatin