4BUI

Crystal structure of human tankyrase 2 in complex with methyl 4-(4- oxo-3,4-dihydroquinazolin-2-yl)benzoate

4BUI の概要

• エントリーDOI: 10.2210/pdb4bui/pdb
• 関連するPDBエントリー: 4BU3 4BU5 4BU6 4BU7 4BU8 4BU9 4BUA 4BUD 4BUE 4BUF 4BUS 4BUT 4BUU 4BUV 4BUW 4BUX 4BUY
• 分子名称: TANKYRASE-2, ZINC ION, SULFATE ION, ... (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)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 55859.34

構造登録者

Haikarainen, T.,Narwal, M.,Lehtio, L. (登録日: 2013-06-20, 公開日: 2013-10-30, 最終更新日: 2023-12-20)

主引用文献

Haikarainen, T.,Koivunen, J.,Narwal, M.,Venkannagari, H.,Obaji, E.,Joensuu, P.,Pihlajaniemi, T.,Lehtio, L.
Para-Substituted 2-Phenyl-3,4-Dihydroquinazolin-4-Ones as Potent and Selective Tankyrase Inhibitors.
Chemmedchem, 8:1978-, 2013

PubMed Abstract: Human tankyrases are attractive drug targets, especially for the treatment of cancer. We identified a set of highly potent tankyrase inhibitors based on a 2-phenyl-3,4-dihydroquinazolin-4-one scaffold. Substitutions at the para position of the scaffold's phenyl group were evaluated as a strategy to increase potency and improve selectivity. The best compounds displayed single-digit nanomolar potencies, and profiling against several human diphtheria-toxin-like ADP-ribosyltransferases revealed that a subset of these compounds are highly selective tankyrase inhibitors. The compounds also effectively inhibit Wnt signaling in HEK293 cells. The binding mode of all inhibitors was studied by protein X-ray crystallography. This allowed us to establish a structural basis for the development of highly potent and selective tankyrase inhibitors based on the 2-phenyl-3,4-dihydroquinazolin-4-one scaffold and outline a rational approach to the modification of other inhibitor scaffolds that bind to the nicotinamide site of the catalytic domain.

PubMed: 24130191
DOI: 10.1002/CMDC.201300337

実験手法

X-RAY DIFFRACTION (1.95 Å)