title: Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity.
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.
authors.affiliation: Department of Biochemistry and Biocenter Oulu, University of Oulu , Oulu 90570, Finland.
authors.forename: Mohit
authors.initials: M
authors.lastname: Narwal
authors.forename: Jarkko
authors.initials: J
authors.lastname: Koivunen
authors.forename: Teemu
authors.initials: T
authors.lastname: Haikarainen
authors.forename: Ezeogo
authors.initials: E
authors.lastname: Obaji
authors.forename: Ongey E
authors.initials: OE
authors.lastname: Legala
authors.forename: Harikanth
authors.initials: H
authors.lastname: Venkannagari
authors.forename: Päivi
authors.initials: P
authors.lastname: Joensuu
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
authors.forename: Lari
authors.initials: L
authors.lastname: Lehtiö
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D047309:Flavones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D057809:HEK293 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007739:L Cells; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D047309:Flavones; D006575:Heterocyclic Compounds, 3-Ring; D007527:Isoenzymes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D038501:Tankyrases; C544261:XAV939; C437334:TNKS2 protein, human; C418109:TNKS protein, human