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Discovery of Tankyrase Inhibiting Flavones with Increased Potency and Isoenzyme Selectivity

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Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu 90570, Finland
Pharmaceutical Sciences, Department of Biosciences, Abo Akademi University, Turku FI-20500, Finland
§ Center for Cell-Matrix Research and Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu 90570, Finland
Department of Chemistry, University of Oulu, Oulu 90570, Finland
*Phone: +358 2 9448 1169. E-mail: [email protected]
Cite this: J. Med. Chem. 2013, 56, 20, 7880–7889
Publication Date (Web):September 26, 2013
Copyright © 2013 American Chemical Society

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    Abstract Image

    Tankyrases are ADP-ribosyltransferases that play key roles in various cellular pathways, including the regulation of cell proliferation, and thus, they are promising drug targets for the treatment of cancer. Flavones have been shown to inhibit tankyrases and we report here the discovery of more potent and selective flavone derivatives. Commercially available flavones with single substitutions were used for structure–activity relationship studies, and cocrystal structures of the 18 hit compounds were analyzed to explain their potency and selectivity. The most potent inhibitors were also tested in a cell-based assay, which demonstrated that they effectively antagonize Wnt signaling. To assess selectivity, they were further tested against a panel of homologous human ADP-ribosyltransferases. The most effective compound, 22 (MN-64), showed 6 nM potency against tankyrase 1, isoenzyme selectivity, and Wnt signaling inhibition. This work forms a basis for rational development of flavones as tankyrase inhibitors and guides the development of other structurally related inhibitors.

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    Figure 1 containing the results of the cell-based assay of all the compounds tested at 5 μM; Figure 2 containing the experimental curves of the key compounds; Table 1 containing the data collection and refinement statistics for the crystal structures; Table 2 containing the conditions used for profiling the ARTD isoenzymes; Table 3 containing supplier information of the tested compounds. This material is available free of charge via the Internet at

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