4N4V

Co-crystal structure of tankyrase 1 with compound 4 [(4S)-3-{trans-4-[6-amino-5-(pyrimidin-2-yl)pyridin-3-yl]cyclohexyl}-5,5-dimethyl-4-phenyl-1,3-oxazolidin-2-one]

4N4V の概要

• エントリーDOI: 10.2210/pdb4n4v/pdb
• 関連するPDBエントリー: 4K4F 4N3R 4N4T
• 分子名称: Tankyrase-1, ZINC ION, (4S)-3-{trans-4-[6-amino-5-(pyrimidin-2-yl)pyridin-3-yl]cyclohexyl}-5,5-dimethyl-4-phenyl-1,3-oxazolidin-2-one, ... (4 entities in total)
• 機能のキーワード: tankyrase, parp, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: O95271
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 51100.56

構造登録者

Huang, X. (登録日: 2013-10-08, 公開日: 2013-12-11, 最終更新日: 2024-02-28)

主引用文献

Huang, H.,Guzman-Perez, A.,Acquaviva, L.,Berry, V.,Bregman, H.,Dovey, J.,Gunaydin, H.,Huang, X.,Huang, L.,Saffran, D.,Serafino, R.,Schneider, S.,Wilson, C.,DiMauro, E.F.
Structure-based design of 2-aminopyridine oxazolidinones as potent and selective tankyrase inhibitors.
ACS Med Chem Lett, 4:1218-1223, 2013

PubMed Abstract: Aberrant activation of the Wnt pathway has been implicated in the development and formation of many cancers. TNKS inhibition has been shown to antagonize Wnt signaling via Axin stabilization in APC mutant colon cancer cell lines. We employed structure-based design to identify a series of 2-aminopyridine oxazolidinones as potent and selective TNKS inhibitors. These compounds exhibited good enzyme and cell potency as well as selectivity over other PARP isoforms. Co-crystal structures of these 2-aminopyridine oxazolidinones complexed to TNKS reveal an induced-pocket binding mode that does not involve interactions with the nicotinamide binding pocket. Oral dosing of lead compounds 3 and 4 resulted in significant effects on several Wnt-pathway biomarkers in a three day DLD-1 mouse tumor PD model.

PubMed: 24900633
DOI: 10.1021/ml4003315

実験手法

X-RAY DIFFRACTION (2 Å)