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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.

Original publication

DOI

10.1021/jm901018f

Type

Journal article

Journal

J Med Chem

Publication Date

22/10/2009

Volume

52

Pages

6369 - 6381

Keywords

Adenosine Triphosphate, Animals, Binding, Competitive, Carbazoles, Cell Line, Tumor, Cell Proliferation, Crystallography, X-Ray, Drug Discovery, Humans, Models, Molecular, Molecular Conformation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-pim-1