2GMX

Selective Aminopyridine-Based C-Jun N-terminal Kinase inhibitors with cellular activity

2GMX の概要

• エントリーDOI: 10.2210/pdb2gmx/pdb
• 関連するPDBエントリー: 2g01
• 分子名称: Mitogen-activated protein kinase 8, C-jun-amino-terminal kinase-interacting protein 1, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: jnk1, c-jun n-terminal kinase, protein kinase jnk1 inhibitors, aminopyridine-based c-jun n-terminal kinase inhibitors, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasm (By similarity): Q9UQF2
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 89785.14

構造登録者

Abad-Zapatero, C. (登録日: 2006-04-07, 公開日: 2006-06-06, 最終更新日: 2023-08-30)

主引用文献

Szczepankiewicz, B.G.,Kosogof, C.,Nelson, L.T.,Liu, G.,Liu, B.,Zhao, H.,Serby, M.D.,Xin, Z.,Liu, M.,Gum, R.J.,Haasch, D.L.,Wang, S.,Clampit, J.E.,Johnson, E.F.,Lubben, T.H.,Stashko, M.A.,Olejniczak, E.T.,Sun, C.,Dorwin, S.A.,Haskins, K.,Abad-Zapatero, C.,Fry, E.H.,Hutchins, C.W.,Sham, H.L.,Rondinone, C.M.,Trevillyan, J.M.
Aminopyridine-Based c-Jun N-Terminal Kinase Inhibitors with Cellular Activity and Minimal Cross-Kinase Activity.
J.Med.Chem., 49:3563-3580, 2006

PubMed Abstract: The c-Jun N-terminal kinases (JNK-1, -2, and -3) are members of the mitogen activated protein (MAP) kinase family of enzymes. They are activated in response to certain cytokines, as well as by cellular stresses including chemotoxins, peroxides, and irradiation. They have been implicated in the pathology of a variety of different diseases with an inflammatory component including asthma, stroke, Alzheimer's disease, and type 2 diabetes mellitus. In this work, high-throughput screening identified a JNK inhibitor with an excellent kinase selectivity profile. Using X-ray crystallography and biochemical screening to guide our lead optimization, we prepared compounds with inhibitory potencies in the low-double-digit nanomolar range, activity in whole cells, and pharmacokinetics suitable for in vivo use. The new compounds were over 1,000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38alpha, and p38delta and showed little inhibitory activity against a panel of 74 kinases.

PubMed: 16759099
DOI: 10.1021/jm060199b

実験手法

X-RAY DIFFRACTION (3.5 Å)