5-(2-Amino-pyrimidin-4-yl)-1H-pyrrole and 2-(2-amino-pyrimidin-4-yl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one derivatives as new classes of selective and orally available Polo-like kinase 1 inhibitors

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• 作者：Michele Caruso^a ; Barbara Valsasina^a ; Dario Ballinari^a ; Jay Bertrand^a ; Maria Gabriella Brasca^a ; Marina Caldarelli^a ; Paolo Cappella^a ; Francesco Fiorentini^b ; Laura M. Gianellini^a ; Alessandra Scolaro^a ; Italo Beria^a ; ^{italo.beria@nervianoms.com}
• 关键词：PLK1 ; Polo-like kinase ; PLK2 and PLK3 ; Cell cycle ; Cellular activity ; Crystal structure
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：1 January, 2012
• 年：2012
• 卷：22
• 期：1
• 页码：96-101
• 全文大小：651 K

文摘

The discovery and characterization of two new chemical classes of potent and selective Polo-like kinase 1 (PLK1) inhibitors is reported. For the most interesting compounds, we discuss the biological activities, crystal structures and preliminary pharmacokinetic parameters. The more advanced compounds inhibit PLK1 in the enzymatic assay at the nM level and exhibit good activity in cell proliferation on A2780 cells. Furthermore, these compounds showed high levels of selectivity on a panel of unrelated kinases, as well as against PLK2 and PLK3 isoforms. Additionally, the compounds show acceptable oral bioavailability in mice making these inhibitors suitable candidates for further in vivo activity studies.