5wal

Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model

spinqualitylabelsall models 5wal, resolution 2.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5wal is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 9ZS Activity: Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [TYK2_HUMAN] Mendelian susceptibility to mycobacterial diseases;Autosomal recessive hyper IgE syndrome. Defects in TYK2 are the cause of protein-tyrosine kinase 2 deficiency (TYK2 deficiency) [MIM:611521]; also known as autosomal recessive hyper-IgE syndrome (HIES) with atypical mycobacteriosis. TYK2 deficiency consists of a primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE. Function [TYK2_HUMAN] Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain. Publication Abstract from PubMed Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients. Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model.,Liang J, Van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair WS, Chang C, Delarosa D, DeVoss J, Driscoll J, Eigenbrot C, Goodacre S, Ghilardi N, MacLeod C, Johnson A, Bir Kohli P, Lai Y, Lin Z, Mantik P, Menghrajani K, Nguyen H, Peng I, Sambrone A, Shia S, Smith J, Sohn S, Tsui V, Ultsch M, Williams K, Wu LC, Yang W, Zhang B, Magnuson S Bioorg Med Chem Lett. 2017 Aug 12. pii: S0960-894X(17)30823-5. doi:, 10.1016/j.bmcl.2017.08.022. PMID:28830649 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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