Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 191, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112148
Keywords
Autoimmune diseases; Covalent JAK3 inhibitors; Cys909; Janus kinase; 4-or 6-phenyl-pyrimidine derivatives
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Funding
- National Natural Science Foundation of China [30973607, 81172934]
- Double First-Class New Drug Development Project of China Pharmaceutical University [CPU2018PZQ15]
- Beijing Municipal Natural Science Foundation [7182115]
- CAMS Innovation Fund for Medical Science [2017-I2M-3-011]
- Drug Innovation Major Project of China, China [2018ZX09711001-003-001]
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As non-receptor tyrosine kinases, Janus kinases (JAKs) have become an attractive target for the treatment of autoimmune diseases and cancers. JAKs play a pivotal role in innate immunity, inflammation, and hematopoiesis by mediating the signaling of numerous cytokines, growth factors, and interferons (IFNs). Selective inhibitors of a variety of JAK members are expected to inhibit pro-inflammatory cytokine-mediated inflammation and immune responses, while preventing targeting other subtypes of JAKs. In this work, poorly selective compounds based on 4- or 6-phenyl-pyrimidine derivatives have been improved to highly potent and selective compounds by designing a covalent binding tether, which attaches to the unique cysteine (Cys909) residue in JAK3. Compound 12 exhibited potent JAK3 inhibitory activity (IC50 = 1.7 nM) with an excellent selectivity profile when compared to the other JAK isoforms (>588-fold). In a cellular assay, compound 12 strongly inhibited JAK3-dependent signaling and T cell proliferation. Moreover, in vivo data revealed that compound 12 significantly suppressed oxazolone (OXZ)-induced delayed hypersensitivity responses in Balb/c mice. Compound 12 also displayed decent pharmacokinetic properties and was suitable for in vivo use. Taken together, these results indicated that compound 12 may be a promising tool compound as a selective JAK3 inhibitor for treating autoimmune diseases. (c) 2020 Elsevier Masson SAS. All rights reserved.
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