4E6D

JAK2 kinase (JH1 domain) triple mutant in complex with compound 7

4E6D の概要

• エントリーDOI: 10.2210/pdb4e6d/pdb
• 関連するPDBエントリー: 4E4L 4E4M 4E4N 4E5W 4E6Q
• 分子名称: Tyrosine-protein kinase JAK2, 3-[(3R)-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-1-yl]-3-oxopropanenitrile, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: jak2, kinase, transferase, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endomembrane system; Peripheral membrane protein (By similarity): O60674
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71158.94

構造登録者

Murray, J.M. (登録日: 2012-03-15, 公開日: 2012-05-30, 最終更新日: 2024-11-06)

主引用文献

Kulagowski, J.J.,Blair, W.,Bull, R.J.,Chang, C.,Deshmukh, G.,Dyke, H.J.,Eigenbrot, C.,Ghilardi, N.,Gibbons, P.,Harrison, T.K.,Hewitt, P.R.,Liimatta, M.,Hurley, C.A.,Johnson, A.,Johnson, T.,Kenny, J.R.,Bir Kohli, P.,Maxey, R.J.,Mendonca, R.,Mortara, K.,Murray, J.,Narukulla, R.,Shia, S.,Steffek, M.,Ubhayakar, S.,Ultsch, M.,van Abbema, A.,Ward, S.I.,Waszkowycz, B.,Zak, M.
Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors.
J.Med.Chem., 55:5901-5921, 2012

PubMed Abstract: A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.

PubMed: 22591402
DOI: 10.1021/jm300438j

実験手法

X-RAY DIFFRACTION (2.22 Å)