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Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling

DOI: 10.1016/j.bmcl.2019.04.008 DOI Help

Authors: Mark Zak (Genentech Inc.) , Emily J. Hanan (Genentech Inc.) , Patrick Lupardus (Genentech Inc.) , David G. Brown (Charles River Laboratories) , Colin Robinson (Charles River Laboratories) , Michael Siu (Genentech Inc.) , Joseph P. Lyssikatos (Genentech Inc.) , F. Anthony Romero (Genentech Inc.) , Guiling Zhao (Genentech Inc.) , Terry Kellar (Genentech Inc.) , Rohan Mendonca (Genentech Inc.) , Nicholas C. Ray (Charles River Laboratories) , Simon C. Goodacre (Charles River Laboratories) , Peter H. Crackett (Charles River Laboratories) , Neville Mclean (Charles River Laboratories) , Christopher A. Hurley (Charles River Laboratories) , Po-wai Yuen (Pharmaron Beijing Co. Ltd.) , Yun-xing Cheng (Pharmaron Beijing Co. Ltd.) , Xiongcai Liu (Pharmaron Beijing Co. Ltd.) , Marya Liimatta (Genentech Inc.) , Pawan Bir Kohli (Genentech Inc.) , Jim Nonomiya (Genentech Inc.) , Gary Salmon (Charles River Laboratories) , Gerry Buckley (Charles River Laboratories) , Julia Lloyd (Charles River Laboratories) , Paul Gibbons (Genentech Inc.) , Nico Ghilardi (Genentech Inc.) , Jane R. Kenny (Genentech Inc.) , Adam Johnson (Genentech Inc.)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters

State: Published (Approved)
Published: April 2019
Diamond Proposal Number(s): 5069 , 14629

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).

Journal Keywords: Janus Kinase; JAK; JAK1; JAK2; Interleukin-13; IL-13; Structure-based design; Asthma; Atopic dermatitis

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)