Synthesis, Kinase Inhibitory Potencies, and in Vitro Antiproliferative Evaluation of New Pim Kinase Inhibitors

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• 作者：Rufine Aku-Gdu ; Emilie Rossignol ; Stphane Azzaro ; Stefan Knapp ; Panagis Filippakopoulos ; Alex N. Bullock ; Jenny Bain ; Philip Cohen ; Michelle Prudhomme ; Fabrice Anizon ; Pascale Moreau
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：October 22, 2009
• 年：2009
• 卷：52
• 期：20
• 页码：6369-6381
• 全文大小：941K
• 年卷期：v.52,no.20(October 22, 2009)
• ISSN：1520-4804

文摘

Members of the Pim kinase family have been identified as promising targets for the development of antitumor agents. After a screening of pyrrolo[2,3-a]- and [3,2-a]carbazole derivatives toward 66 protein kinases, we identified pyrrolo[2,3-a]carbazole as a new scaffold to design potent Pim kinase inhibitors. In particular, compound 9 was identified as a low nM selective Pim inhibitor. Additionally, several pyrrolo[2,3-a]carbazole derivatives showed selectivity for Pim-1 and Pim-3 over Pim-2. In vitro antiproliferative activities of 9 and 28, the most potent Pim inhibitors identified, were evaluated toward three human solid cancer cell lines (PA1, PC3, and DU145) and one human fibroblast primary culture, revealing IC₅₀ values in the micromolar range. Finally, the crystal structure of Pim-1 complexed with lead compound 9 was determined. The structure revealed a non-ATP mimetic binding mode with no hydrogen bonds formed with the kinase hinge region and explained the selectivity of pyrrolo[2,3-a]carbazole derivatives for Pim kinases.