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Bioorg Med Chem Lett. 2019 Jun 15;29(12):1522-1531. doi: 10.1016/j.bmcl.2019.04.008. Epub 2019 Apr 4.

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

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Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address:
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Charles River Laboratories, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
Pharmaron Beijing Co. Ltd., 6 Taihe Road, BDA, Beijing 100176, PR China.


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).


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


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