4L2F

Tankyrase 2 in complex with 6-chloro flavone

Summary for 4L2F

• Entry DOI: 10.2210/pdb4l2f/pdb
• Related: 4BS4 4HKI 4KZL 4KZQ 4KZU 4L09 4L0B 4L0I 4L0S 4L0T 4L0V 4L10 4L2G 4L2K 4L31 4L32 4L33 4L34
• Descriptor: Tankyrase-2, 6-chloro-2-phenyl-4H-chromen-4-one, ZINC ION, ... (7 entities in total)
• Functional Keywords: protein-ligand complex, diphtheria toxin like fold, transferase, adp-ribosylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: Q9H2K2 Q9H2K2
• Total number of polymer chains: 4
• Total formula weight: 55499.37

Authors

Narwal, M.,Haikarainen, T.,Lehtio, L. (deposition date: 2013-06-04, release date: 2013-10-30, Last modification date: 2023-09-20)

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., 56:7880-7889, 2013

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: 24116873
DOI: 10.1021/jm401463y

Experimental method

X-RAY DIFFRACTION (2.05 Å)