4BS4
Crystal structure of human tankyrase 2 in complex with 4'-isopropylflavone
Summary for 4BS4
| Entry DOI | 10.2210/pdb4bs4/pdb |
| Descriptor | TANKYRASE-2, ZINC ION, SULFATE ION, ... (7 entities in total) |
| Functional Keywords | transferase, protein-ligand complex, diphtheria toxin like fold, adp- ribosylation, transferase-transferase inhibitor complex |
| Biological source | HOMO SAPIENS (HUMAN) |
| Total number of polymer chains | 2 |
| Total formula weight | 55947.57 |
| Authors | Haikarainen, T.,Narwal, M.,Lehtio, L. (deposition date: 2013-06-07, release date: 2013-10-30, Last modification date: 2024-05-08) |
| Primary citation | Narwal, M.,Koivunen, J.,Haikarainen, T.,Obaji, E.,Legala, O.E.,Venkannagari, H.,Joensuu, P.,Pihlajaniemi, T.,Lehtio, L. Discovery of Tankyrase Inhibiting Flavones with Increased Potency and Isoenzyme Selectivity. J.Med.Chem., 56:7880-, 2013 Cited by PubMed 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. PubMed: 24116873DOI: 10.1021/JM401463Y PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.89 Å) |
Structure validation
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