6x8e
Crystal structure of JAK2 with Compound 11
Structural highlights
Publication Abstract from PubMedTyrosine kinase 2 (TYK2) is a member of the JAK kinase family that regulates signal transduction downstream of receptors for the IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, respectively. On the basis of human genetic and emerging clinical data, a selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering a potentially differentiated clinical profile compared to currently approved JAK inhibitors. The discovery of an ATP-competitive pyrazolopyrazinyl series of TYK2 inhibitors was accomplished through computational and structurally enabled design starting from a known kinase hinge binding motif. With understanding of PK/PD relationships, a target profile balancing TYK2 potency and selectivity over off-target JAK2 was established. Lead optimization involved modulating potency, selectivity, and ADME properties which led to the identification of the clinical candidate PF-06826647 (22). Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases.,Gerstenberger BS, Ambler C, Arnold EP, Banker ME, Brown MF, Clark JD, Dermenci A, Dowty ME, Fensome A, Fish S, Hayward MM, Hegen M, Hollingshead BD, Knafels JD, Lin DW, Lin TH, Owen DR, Saiah E, Sharma R, Vajdos FF, Xing L, Yang X, Yang X, Wright SW J Med Chem. 2020 Aug 25. doi: 10.1021/acs.jmedchem.0c00948. PMID:32787094[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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