6HZV

HUMAN JAK3 IN COMPLEX WITH LASW959 PROTEIN IN COMPLEX WITH LIGAND

6HZV の概要

• エントリーDOI: 10.2210/pdb6hzv/pdb
• 分子名称: Tyrosine-protein kinase JAK3, 3-[7-(2-hydroxyethyl)-9-(oxan-4-yl)-8-oxidanylidene-purin-2-yl]imidazo[1,2-a]pyridine-6-carbonitrile (3 entities in total)
• 機能のキーワード: protein kinase, janus kinase, jak3, protein binding, proteros biostructures gmbh
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 132382.84

構造登録者

Lozoya, E.,Segarra, V.,Bach, J.,Jestel, A.,Lammens, A.,Blaesse, M. (登録日: 2018-10-24, 公開日: 2019-10-23, 最終更新日: 2024-01-24)

主引用文献

Bach, J.,Eastwood, P.,Gonzalez, J.,Gomez, E.,Alonso, J.A.,Fonquerna, S.,Lozoya, E.,Orellana, A.,Maldonado, M.,Calaf, E.,Alberti, J.,Perez, J.,Andres, A.,Prats, N.,Carreno, C.,Calama, E.,De Alba, J.,Calbet, M.,Miralpeix, M.,Ramis, I.
Identification of 2-Imidazopyridine and 2-Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) Inhibitors for the Inhaled Treatment of Respiratory Diseases.
J.Med.Chem., 62:9045-9060, 2019

PubMed Abstract: Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacological evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compounds of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biology studies led to the discovery of pyridone , a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.

PubMed: 31609613
DOI: 10.1021/acs.jmedchem.9b00533

実験手法

X-RAY DIFFRACTION (2.46 Å)