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ID: ALA4673239
Journal: J Med Chem
Title: Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases.
Authors: 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
Abstract: Tyrosine 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).
CiteXplore: 32787094