8s98

Crystal structure of the TYK2 pseudokinase domain in complex with compound 8

spinqualitylabelsall models 8s98, resolution 1.87Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8s98 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.87Å Ligands: CSO, ZRU Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed TYK2 is a key mediator of IL12, IL23, and type I interferon signaling, and 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 genome-wide association studies and clinical results, TYK2 inhibition through small molecules is an attractive therapeutic strategy to treat these diseases. Herein, we report the discovery of a series of highly selective pseudokinase (Janus homology 2, JH2) domain inhibitors of TYK2 enzymatic activity. A computationally enabled design strategy, including the use of FEP+, was instrumental in identifying a pyrazolo-pyrimidine core. We highlight the utility of computational physics-based predictions used to optimize this series of molecules to identify the development candidate 30, a potent, exquisitely selective cellular TYK2 inhibitor that is currently in Phase 2 clinical trials for the treatment of psoriasis and psoriatic arthritis. Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279.,Leit S, Greenwood J, Carriero S, Mondal S, Abel R, Ashwell M, Blanchette H, Boyles NA, Cartwright M, Collis A, Feng S, Ghanakota P, Harriman GC, Hosagrahara V, Kaila N, Kapeller R, Rafi SB, Romero DL, Tarantino PM, Timaniya J, Toms AV, Wester RT, Westlin W, Srivastava B, Miao W, Tummino P, McElwee JJ, Edmondson SD, Masse CE J Med Chem. 2023 Aug 10;66(15):10473-10496. doi: 10.1021/acs.jmedchem.3c00600. , Epub 2023 Jul 10. PMID:37427891 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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