| Literature DB >> 32787094 |
Brian S Gerstenberger1, Catherine Ambler2, Eric P Arnold2, Mary-Ellen Banker2, Matthew F Brown2, James D Clark1, Alpay Dermenci2, Martin E Dowty1, Andrew Fensome1, Susan Fish1, Matthew M Hayward2, Martin Hegen1, Brett D Hollingshead1, John D Knafels2, David W Lin2, Tsung H Lin1, Dafydd R Owen1, Eddine Saiah1, Raman Sharma2, Felix F Vajdos2, Li Xing1, Xiaojing Yang2, Xin Yang2, Stephen W Wright2.
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).Entities:
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Year: 2020 PMID： 32787094 DOI： 10.1021/acs.jmedchem.0c00948
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446