6HZU

HUMAN JAK1 IN COMPLEX WITH LASW1393

Summary for 6HZU

• Entry DOI: 10.2210/pdb6hzu/pdb
• Descriptor: Tyrosine-protein kinase JAK1, 2-[4-[8-oxidanylidene-2-[(~{E})-(2-oxidanylidenepyridin-3-ylidene)amino]-7~{H}-purin-9-yl]cyclohexyl]ethanenitrile (3 entities in total)
• Functional Keywords: janus kinase, jak1, kinase domain, proteros biostructures gmbh, protein binding
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 70219.93

Authors

Lozoya, E.,Segarra, V.,Bach, J.,Jestel, A.,Lammens, A.,Blaesse, M. (deposition date: 2018-10-24, release date: 2019-10-23, Last modification date: 2024-10-09)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.2 Å)