Discovery of New Inhibitors of Cdc25B Dual Specificity Phosphatases by Structure-Based Virtual Screening

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• 作者：Antonio Lavecchia ; Carmen Di Giovanni ; Ada Pesapane ; Nunzia Montuori ; Pia Ragno ; Nicola Massimiliano Martucci ; Mariorosario Masullo ; Emmanuele De Vendittis ; Ettore Novellino
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：55
• 期：9
• 页码：4142-4158
• 全文大小：793K
• 年卷期：v.55,no.9(May 10, 2012)
• ISSN：1520-4804

文摘

Cell division cycle 25 (Cdc25) proteins are highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases and represent attractive drug targets for anticancer therapies. To discover more potent and diverse inhibitors of Cdc25 biological activity, virtual screening was performed by docking 2.1 million compounds into the Cdc25B active site. An initial subset of top-ranked compounds was selected and assayed, and 15 were found to have enzyme inhibition activity at micromolar concentration. Among these, four structurally diverse inhibitors with a different inhibition profile were found to inhibit human MCF-7, PC-3, and K562 cancer cell proliferation and significantly affect the cell cycle progression. A subsequent hierarchical similarity search with the most active reversible Cdc25B inhibitor found led to the identification of an additional set of 19 ligands, three of which were confirmed as Cdc25B inhibitors with IC₅₀ values of 7.9, 4.2, and 9.9 渭M, respectively.