4MSG

Crystal structure of tankyrase 1 with compound 22

4MSG の概要

• エントリーDOI: 10.2210/pdb4msg/pdb
• 関連するPDBエントリー: 4I9I 4MSK
• 分子名称: Tankyrase-1, ZINC ION, 3-[(4-oxo-3,4-dihydroquinazolin-2-yl)sulfanyl]-N-[trans-4-(5-phenyl-1,3,4-oxadiazol-2-yl)cyclohexyl]propanamide, ... (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: 51164.61

構造登録者

Huang, X. (登録日: 2013-09-18, 公開日: 2013-12-25, 最終更新日: 2024-02-28)

主引用文献

Hua, Z.,Bregman, H.,Buchanan, J.L.,Chakka, N.,Guzman-Perez, A.,Gunaydin, H.,Huang, X.,Gu, Y.,Berry, V.,Liu, J.,Teffera, Y.,Huang, L.,Egge, B.,Emkey, R.,Mullady, E.L.,Schneider, S.,Andrews, P.S.,Acquaviva, L.,Dovey, J.,Mishra, A.,Newcomb, J.,Saffran, D.,Serafino, R.,Strathdee, C.A.,Turci, S.M.,Stanton, M.,Wilson, C.,Dimauro, E.F.
Development of novel dual binders as potent, selective, and orally bioavailable tankyrase inhibitors.
J.Med.Chem., 56:10003-10015, 2013

PubMed Abstract: Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting β-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.

PubMed: 24294969
DOI: 10.1021/jm401317z

実験手法

X-RAY DIFFRACTION (1.8 Å)