3LHJ

Crystal Structure of p38a Mitogen-Activated Protein Kinase in Complex with a Pyrazolopyridinone Inhibitor.

3LHJ の概要

• エントリーDOI: 10.2210/pdb3lhj/pdb
• 関連するPDBエントリー: 1YQJ 3DS6 3DT1 3GFE 3ITZ
• 分子名称: Mitogen-activated protein kinase 14, N-cyclopropyl-3-[1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl]-4-methylbenzamide (3 entities in total)
• 機能のキーワード: serine/threonine-protein kinase, transferase, alternative splicing, atp-binding, cytoplasm, kinase, nucleotide-binding, nucleus, phosphoprotein, polymorphism
• 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: 42433.38

構造登録者

Mohr, C.,Jordan, S. (登録日: 2010-01-22, 公開日: 2010-04-14, 最終更新日: 2024-02-21)

主引用文献

Pettus, L.H.,Wurz, R.P.,Xu, S.,Herberich, B.,Henkle, B.,Liu, Q.,McBride, H.J.,Mu, S.,Plant, M.H.,Saris, C.J.,Sherman, L.,Wong, L.M.,Chmait, S.,Lee, M.R.,Mohr, C.,Hsieh, F.,Tasker, A.S.
Discovery and evaluation of 7-alkyl-1,5-bis-aryl-pyrazolopyridinones as highly potent, selective, and orally efficacious inhibitors of p38alpha mitogen-activated protein kinase.
J.Med.Chem., 53:2973-2985, 2010

PubMed Abstract: The p38alpha mitogen-activated protein (MAP) kinase is a central signaling molecule in many proinflammatory pathways, regulating the cellular response to a multitude of external stimuli including heat, ultraviolet radiation, osmotic shock, and a variety of cytokines especially interleukin-1beta and tumor necrosis factor alpha. Thus, inhibitors of this enzyme are postulated to have significant therapeutic potential for the treatment of rheumatoid arthritis, inflammatory bowel disease, and Crohn's disease, as well as other diseases where aberrant cytokine signaling is the driver of disease. In this communication, we describe a novel class of 7-alkyl-1,5-bis-aryl-pyrazolopyridinone-based p38alpha inhibitors. In particular, compound 3f is highly potent in the enzyme and cell-based assays, selective in an Ambit kinase screen, and efficacious (ED(50) < or = 0.01 mg/kg) in the rat collagen induced arthritis (CIA) model.

PubMed: 20218619
DOI: 10.1021/jm100095x

実験手法

X-RAY DIFFRACTION (3.31 Å)