3MW1

p38 kinase Crystal structure in complex with small molecule inhibitor

3MW1 の概要

• エントリーDOI: 10.2210/pdb3mw1/pdb
• 関連するPDBエントリー: 3HRB
• 分子名称: Mitogen-activated protein kinase 14, 8-(2,6-dichlorophenyl)-4-(2,4-difluorophenyl)-2-piperidin-4-yl-1,7-naphthyridine 7-oxide (3 entities in total)
• 機能のキーワード: p38 map kinase, transferase, inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm (By similarity): Q16539
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41698.34

構造登録者

Segarra, V.,Caturla, F.,Lumeras, W.,Roca, R.,Fisher, M.,Lamers, M. (登録日: 2010-05-05, 公開日: 2011-04-27, 最終更新日: 2023-11-01)

主引用文献

Lumeras, W.,Vidal, L.,Vidal, B.,Balague, C.,Orellana, A.,Maldonado, M.,Dominguez, M.,Segarra, V.,Caturla, F.
1,7-Naphthyridine 1-Oxides as Novel Potent and Selective Inhibitors of p38 Mitogen Activated Protein Kinase
J.Med.Chem., 54:7899-7910, 2011

PubMed Abstract: The design, synthesis, and ability to inhibit p38α MAP kinase by a novel series of naphthyridine N-oxides will be described. Some of these compounds showed a significant reduction in the LPS-induced TNFα production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for its marked selectivity against other related kinases. After an extensive SAR exercise, several compounds from this series were identified as very potent p38α inhibitors. In vivo efficacy of some derivatives was demonstrated to reduce TNFα levels in an acute murine model of inflammation (ED(50) = 0.5 mg/kg in LPS-induced TNFα production when dosed orally 1.5 h prior to LPS administration). The oral efficacy was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) < 1 mg/kg).

PubMed: 21999461
DOI: 10.1021/jm200975u

実験手法

X-RAY DIFFRACTION (2.8 Å)