Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases
| Autor: | Dafydd R. Owen, James D. Clark, Xiaojing Yang, Eddine Saiah, Martin Hegen, Brian S. Gerstenberger, Felix Vajdos, Catherine M. Ambler, Li Xing, Alpay Dermenci, Tsung H. Lin, Matthew Merrill Hayward, Raman Sharma, Xin Yang, David W. Lin, John D. Knafels, Eric P. Arnold, Mary-Ellen Banker, Stephen W. Wright, Martin E. Dowty, Brett D. Hollingshead, Andrew Fensome, Susan Fish, Matthew Frank Brown |
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| Rok vydání: | 2020 |
| Předmět: |
Mice
Transgenic 01 natural sciences Protein Structure Secondary Autoimmune Diseases 03 medical and health sciences Mice Interferon Drug Discovery medicine Animals Humans Receptor Protein Kinase Inhibitors 030304 developmental biology ADME TYK2 Kinase 0303 health sciences Janus kinase 2 biology Chemistry Kinase 0104 chemical sciences 010404 medicinal & biomolecular chemistry Tyrosine kinase 2 Cancer research biology.protein Microsomes Liver Molecular Medicine Signal transduction Janus kinase medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 63(22) |
| ISSN: | 1520-4804 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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