4KZU

Crystal structure of human tankyrase 2 in complex with 4' -bromo flavone

4KZU の概要

• エントリーDOI: 10.2210/pdb4kzu/pdb
• 関連するPDBエントリー: 4BS4 4HKI 4KZL 4KZQ 4L09 4L0B 4L0I 4L0S 4L0T 4L0V 4L10 4L2F 4L2G 4L2K 4L31 4L32 4L33 4L34
• 分子名称: Tankyrase-2, 2-(4-bromophenyl)-4H-chromen-4-one, ZINC ION, ... (7 entities in total)
• 機能のキーワード: protein-ligand complex, diphtheria toxin like fold, transferase, adp-ribosylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasm: Q9H2K2 Q9H2K2
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 55844.96

構造登録者

Narwal, M.,Haikarainen, T.,Lehtio, L. (登録日: 2013-05-30, 公開日: 2013-10-30, 最終更新日: 2023-09-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.1 Å)