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7UYS

Crystal structure of TYK2 kinase domain in complex with compound 16

Summary for 7UYS
Entry DOI10.2210/pdb7uys/pdb
DescriptorNon-receptor tyrosine-protein kinase TYK2, 2-(2,6-difluorophenyl)-4-(4-methoxyanilino)-5H-pyrrolo[3,4-d]pyrimidin-5-one (3 entities in total)
Functional Keywordsnon-receptor tyrosine-protein kinase 2, transferase-transferase inhibitor complex, transferase/transferase inhibitor
Biological sourceHomo sapiens (human)
Total number of polymer chains1
Total formula weight34009.69
Authors
Primary citationLeit, S.,Greenwood, J.R.,Mondal, S.,Carriero, S.,Dahlgren, M.,Harriman, G.C.,Kennedy-Smith, J.J.,Kapeller, R.,Lawson, J.P.,Romero, D.L.,Toms, A.V.,Shelley, M.,Wester, R.T.,Westlin, W.,McElwee, J.J.,Miao, W.,Edmondson, S.D.,Masse, C.E.
Potent and selective TYK2-JH1 inhibitors highly efficacious in rodent model of psoriasis.
Bioorg.Med.Chem.Lett., 73:128891-128891, 2022
Cited by
PubMed Abstract: TYK2 is a member of the JAK family of kinases and a key mediator of IL-12, IL-23, and type I interferon signaling. These cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genetic association studies, TYK2 inhibition is an attractive therapeutic strategy for these diseases. Herein, we report the discovery of a series of highly selective catalytic site TYK2 inhibitors designed using FEP+ and structurally enabled design starting from a virtual screen hit. We highlight the structure-based optimization to identify a lead candidate 30, a potent cellular TYK2 inhibitor with excellent selectivity, pharmacokinetic properties, and in vivo efficacy in a mouse psoriasis model.
PubMed: 35842205
DOI: 10.1016/j.bmcl.2022.128891
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.15 Å)
Structure validation

226707

數據於2024-10-30公開中

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