Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling. Issue 12 (15th June 2019)

• Record Type: Journal Article
• Authors: Zak, Mark; Hanan, Emily J.; Lupardus, Patrick; Brown, David G.; Robinson, Colin; Siu, Michael; Lyssikatos, Joseph P.; Romero, F. Anthony; Zhao, Guiling; Kellar, Terry; Mendonca, Rohan; Ray, Nicholas C.; Goodacre, Simon C.; Crackett, Peter H.; McLean, Neville; Hurley, Christopher A.; Yuen, Po-wai; Cheng, Yun-Xing; Liu, Xiongcai; Liimatta, Marya; Kohli, Pawan Bir; Nonomiya, Jim; Salmon, Gary; Buckley, Gerry; Lloyd, Julia; Gibbons, Paul; Ghilardi, Nico; Kenny, Jane R.; Johnson, Adam
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 12(2019)
• Page Start: 1522
• Page End: 1531
• Publication Date: 2019-06-15
• Subjects: Janus Kinase -- JAK -- JAK1 -- JAK2 -- Interleukin-13 -- IL-13 -- Structure-based design -- Asthma -- Atopic dermatitis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.04.008
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50 's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).