1. Identification of N-Methyl Nicotinamide and N-Methyl Pyridazine-3-Carboxamide Pseudokinase Domain Ligands as Highly Selective Allosteric Inhibitors of Tyrosine Kinase 2 (TYK2)
- Author
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Yanlei Zhang, Jeffrey Tredup, Mertzman Michael E, Nelly Aranibar, Kim W. McIntyre, Kathleen M. Gillooly, Jodi K. Muckelbauer, James R. Burke, Lihong Cheng, Joann Strnad, Celia D’Arienzo, Dawn Mulligan, Stephen T. Wrobleski, Charu Chaudhry, Adriana Zupa-Fernandez, Percy H. Carter, Dianlin Xie, Manoj Chiney, Elizabeth M. Heimrich, Moslin Ryan M, Christine Huang, Xiaoxia Yang, Shuqun Lin, David S. Weinstein, Tokarski John S, Chiehying Chang, Louis J. Lombardo, Huadong Sun, and Steven H. Spergel
- Subjects
Nicotinamide ,medicine.drug_class ,Allosteric regulation ,Carboxamide ,Pyridazine ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Tyrosine kinase 2 ,Drug Discovery ,medicine ,Molecular Medicine ,Structure–activity relationship ,Transferase ,Tyrosine kinase - Abstract
As a member of the Janus (JAK) family of nonreceptor tyrosine kinases, TYK2 plays an important role in mediating the signaling of pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide 4, identified by a SPA-based high-throughput screen targeting the TYK2 pseudokinase domain, potently inhibits IL-23 and IFNα signaling in cellular assays. The described work details the optimization of this poorly selective hit (4) to potent and selective molecules such as 47 and 48. The discoveries described herein were critical to the eventual identification of the clinical TYK2 JH2 inhibitor (see following report in this issue). Compound 48 provided robust inhibition in a mouse IL-12-induced IFNγ pharmacodynamic model as well as efficacy in an IL-23 and IL-12-dependent mouse colitis model. These results demonstrate the ability of TYK2 JH2 domain binders to provide a highly selective alternative to conventional TYK2 orthosteric inhibitors.
- Published
- 2019