8RPN

hJAK3 in complex with LAW931 inhibitor

This is a non-PDB format compatible entry.

Summary for 8RPN

• Entry DOI: 10.2210/pdb8rpn/pdb
• Descriptor: Tyrosine-protein kinase JAK3, 3-[4-[[(3~{R})-1-(2-cyanoethanoyl)piperidin-3-yl]amino]pyrimidin-2-yl]imidazo[1,2-a]pyridine-6-carbonitrile (3 entities in total)
• Functional Keywords: inhibitor, complex, kinase, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 137640.55

Authors

Lozoya, E.,Bach, J.,Lammens, A. (deposition date: 2024-01-16, release date: 2026-09-02, Last modification date: 2026-09-09)

Primary citation

Bach, J.,Perez, D.,Esteve, C.,Llera, O.,Taboada, L.,Eastwood, P.R.,Gonzalez, J.,Pages, L.,Lopez, B.,Ramon, R.,Grau, L.,Ortega, A.,Gonzalez, A.,Biosca, F.,Serrat, J.,Connolly, S.,Fonquerna, S.,Beswick, P.,Gracia, J.,Lozoya, E.,Huerta, J.M.,Espinosa, S.,Orellana, A.,Maldonado, M.,Perez-Andres, J.,Rodergas Mir, C.,Calaf, E.,Alberti, J.,Auli, M.,Carreno, C.,Calama, E.,De Alba, J.,Miralpeix, M.,Calbet, M.,Ramis, I.
Discovery of LAS194046: A Potent and Selective pan-Janus Kinase (JAK) Inhibitor with a Suitable Profile for Inhaled Administration.
J.Med.Chem., 69:19601-19632, 2026

PubMed Abstract: Relevant cytokines involved in inflammatory processes in asthma and Chronic Obstructive Pulmonary Disease (COPD) signal through the Janus kinase (JAK) proteins. Therefore, a JAK inhibitor blocking multiple cytokine signaling pathways constitutes a potential new anti-inflammatory therapy for these diseases. Herein is described the discovery and progression of a novel series of pyrazolo[1,5-a]pyridine JAK inhibitors with a profile suitable for inhaled administration. Structural biology-guided design was used to improve potency, kinase selectivity, and lung retention of initial compounds, leading to the identification of compound 18 (LAS194046), a potent and selective pan-JAK inhibitor with an excellent profile for inhaled administration and proven efficacy in the ovalbumin (OVA)-induced airway inflammation model in rat by the inhaled route. As part of the optimization process leading to 18, the relevance of several physicochemical properties in lung retention has also been analyzed.

PubMed: 42679145
DOI: 10.1021/acs.jmedchem.6c00169

Experimental method

X-RAY DIFFRACTION (2.72 Å)