6N7B

Structure of the human JAK1 kinase domain with compound 38

Summary for 6N7B

• Entry DOI: 10.2210/pdb6n7b/pdb
• Descriptor: Tyrosine-protein kinase JAK1, N-[3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl]-1H-pyrazolo[4,3-c]pyridine-7-carboxamide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: jak1, il13, il-13, jak2, jak3, tyk2, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 35313.59

Authors

Lupardus, P.J.,Brown, D. (deposition date: 2018-11-27, release date: 2019-04-24, Last modification date: 2024-11-06)

Primary citation

Zak, M.,Hanan, E.J.,Lupardus, P.,Brown, D.G.,Robinson, C.,Siu, M.,Lyssikatos, J.P.,Romero, F.A.,Zhao, G.,Kellar, T.,Mendonca, R.,Ray, N.C.,Goodacre, S.C.,Crackett, P.H.,McLean, N.,Hurley, C.A.,Yuen, P.W.,Cheng, Y.X.,Liu, X.,Liimatta, M.,Kohli, P.B.,Nonomiya, J.,Salmon, G.,Buckley, G.,Lloyd, J.,Gibbons, P.,Ghilardi, N.,Kenny, J.R.,Johnson, A.
Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling.
Bioorg.Med.Chem.Lett., 29:1522-1531, 2019

PubMed 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 IC'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).

PubMed: 30981576
DOI: 10.1016/j.bmcl.2019.04.008

Experimental method

X-RAY DIFFRACTION (1.81 Å)