6QXU

Human TNKS1 in complex with 6,8-Difluoro-2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-3H-quinazolin-4-one

6QXU の概要

• エントリーDOI: 10.2210/pdb6qxu/pdb
• 分子名称: Poly [ADP-ribose] polymerase tankyrase-1, BETA-MERCAPTOETHANOL, 6,8-bis(fluoranyl)-2-[4-(2-oxidanylpropan-2-yl)phenyl]-3~{H}-quinazolin-4-one, ... (5 entities in total)
• 機能のキーワード: tankyrase, parp, inhibitor, transferase-transferase inhibitor complex, transferase, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24672.30

構造登録者

Musil, D.,Lehmann, D.,Buchstaller, H.-P. (登録日: 2019-03-08, 公開日: 2019-08-14, 最終更新日: 2024-05-01)

主引用文献

Buchstaller, H.P.,Anlauf, U.,Dorsch, D.,Kuhn, D.,Lehmann, M.,Leuthner, B.,Musil, D.,Radtki, D.,Ritzert, C.,Rohdich, F.,Schneider, R.,Esdar, C.
Discovery and Optimization of 2-Arylquinazolin-4-ones into a Potent and Selective Tankyrase Inhibitor Modulating Wnt Pathway Activity.
J.Med.Chem., 62:7897-7909, 2019

PubMed Abstract: Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological targets that recently gained interest for anticancer therapy in Wnt pathway dependent tumors. 2-Aryl-quinazolinones were identified and optimized into potent tankyrase inhibitors through SAR exploration around the quinazolinone core and the 4'-position of the phenyl residue. These efforts were supported by analysis of TNKS X-ray and WaterMap structures and resulted in compound , a potent, selective tankyrase inhibitor with favorable pharmacokinetic properties. The X-ray structure of in complex with TNKS1 was solved and confirmed the design hypothesis. Modulation of Wnt pathway activity was demonstrated with this compound in a colorectal xenograft model .

PubMed: 31381853
DOI: 10.1021/acs.jmedchem.9b00656

実験手法

X-RAY DIFFRACTION (1.2 Å)