Inhibitor of Ovarian Cancer Cells Growth by Virtual Screening: A New Thiazole Derivative Targeting Human Thymidylate Synthase

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• 作者：Emanuele Carosati ; Anna Tochowicz ; Gaetano Marverti ; Giambattista Guaitoli ; Paolo Benedetti ; Stefania Ferrari ; Robert M. Stroud ; Janet Finer-Moore ; Rosaria Luciani ; Davide Farina ; Gabriele Cruciani ; M. Paola Costi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：10272-10276
• 全文大小：318K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

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 渭M 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.