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

Autor: Zak M; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: mzak@gene.com., Hanan EJ; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Lupardus P; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Brown DG; Charles River Laboratories, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom., Robinson C; Charles River Laboratories, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom., Siu M; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Lyssikatos JP; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Romero FA; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Zhao G; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Kellar T; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Mendonca R; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Ray NC; Charles River Laboratories, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom., Goodacre SC; Charles River Laboratories, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom., Crackett PH; Charles River Laboratories, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom., McLean N; Charles River Laboratories, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom., Hurley CA; Charles River Laboratories, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom., Yuen PW; Pharmaron Beijing Co. Ltd., 6 Taihe Road, BDA, Beijing 100176, PR China., Cheng YX; Pharmaron Beijing Co. Ltd., 6 Taihe Road, BDA, Beijing 100176, PR China., Liu X; Pharmaron Beijing Co. Ltd., 6 Taihe Road, BDA, Beijing 100176, PR China., Liimatta M; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Kohli PB; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Nonomiya J; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Salmon G; Charles River Laboratories, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom., Buckley G; Charles River Laboratories, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom., Lloyd J; Charles River Laboratories, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom., Gibbons P; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Ghilardi N; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Kenny JR; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Johnson A; Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Jun 15; Vol. 29 (12), pp. 1522-1531. Date of Electronic Publication: 2019 Apr 04.
DOI: 10.1016/j.bmcl.2019.04.008
Abstrakt: 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 IC 50 '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).
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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