6n78 | pdb_00006n78

Structure of the human JAK1 kinase domain with compound 21

spinqualitylabelsall models 6n78, resolution 1.83Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6n78 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL, KEP NonStd Res: PTR Gene: JAK1, JAK1A, JAK1B (HUMAN) Activity: Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [JAK1_HUMAN] Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor. Publication Abstract from PubMed 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). Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling.,Zak M, Hanan EJ, Lupardus P, Brown DG, Robinson C, Siu M, Lyssikatos JP, Romero FA, Zhao G, Kellar T, Mendonca R, Ray NC, Goodacre SC, Crackett PH, McLean N, Hurley CA, Yuen PW, Cheng YX, Liu X, Liimatta M, Kohli PB, Nonomiya J, Salmon G, Buckley G, Lloyd J, Gibbons P, Ghilardi N, Kenny JR, Johnson A Bioorg Med Chem Lett. 2019 Apr 4. pii: S0960-894X(19)30217-3. doi:, 10.1016/j.bmcl.2019.04.008. PMID:30981576 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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