5AKU

Crystal structure of TNKS2 in complex with 2-(4-tert-butylphenyl)-1,2, 3,4-tetrahydroquinazolin-4-one

5AKU の概要

• エントリーDOI: 10.2210/pdb5aku/pdb
• 関連するPDBエントリー: 5AKW 5AL1 5AL2 5AL3 5AL4 5AL5
• 分子名称: TANKYRASE-2, SULFATE ION, 2-(4-tert-butylphenyl)-1,4-dihydroquinazolin-4-one, ... (6 entities in total)
• 機能のキーワード: transferase, protein-ligand complex, diphtheria toxin like fold, adp- ribosylation, transferase-transferase inhibitor complex
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cytoplasm: Q9H2K2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 56039.67

構造登録者

Nkizinkiko, Y.,Lehtio, L. (登録日: 2015-03-05, 公開日: 2015-07-29, 最終更新日: 2024-01-10)

主引用文献

Nkizinkiko, Y.,Suneel Kumar, B.V.S.,Jeankumar, V.U.,Haikarainen, T.,Koivunen, J.,Madhuri, C.,Yogeeswari, P.,Venkannagari, H.,Obaji, E.,Pihlajaniemi, T.,Sriram, D.,Lehtio, L.
Discovery of Potent and Selective Nonplanar Tankyrase Inhibiting Nicotinamide Mimics.
Bioorg.Med.Chem., 23:4139-, 2015

PubMed Abstract: Diphtheria toxin-like ADP-ribosyltransferases catalyse a posttranslational modification, ADP-ribosylation and form a protein family of 17 members in humans. Two of the family members, tankyrases 1 and 2, are involved in several cellular processes including mitosis and Wnt/β-catenin signalling pathway. They are often over-expressed in cancer cells and have been linked with the survival of cancer cells making them potential therapeutic targets. In this study, we identified nine tankyrase inhibitors through virtual and in vitro screening. Crystal structures of tankyrase 2 with the compounds showed that they bind to the nicotinamide binding site of the catalytic domain. Based on the co-crystal structures we designed and synthesized a series of tetrahydroquinazolin-4-one and pyridopyrimidin-4-one analogs and were subsequently able to improve the potency of a hit compound almost 100-fold (from 11 μM to 150 nM). The most potent compounds were selective towards tankyrases over a panel of other human ARTD enzymes. They also inhibited Wnt/β-catenin pathway in a cell-based reporter assay demonstrating the potential usefulness of the identified new scaffolds for further development.

PubMed: 26183543
DOI: 10.1016/J.BMC.2015.06.063

実験手法

X-RAY DIFFRACTION (1.8 Å)