Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity

Mohit Narwal, Jarkko Koivunen, Teemu Haikarainen, Ezeogo Obaji, Ongey E. Legala, Harikanth Venkannagari, Päivi Joensuu, Taina Pihlajaniemi, Lari Lehtiö

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7880-7889
Number of pages10
JournalJournal of medicinal chemistry
Volume56
Issue number20
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Narwal, M., Koivunen, J., Haikarainen, T., Obaji, E., Legala, O. E., Venkannagari, H., Joensuu, P., Pihlajaniemi, T., & Lehtiö, L. (2013). Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity. Journal of medicinal chemistry, 56(20), 7880-7889. https://doi.org/10.1021/jm401463y