2. Academic Validation
  3. Identification of N-Methyl Nicotinamide and N-Methyl Pyridazine-3-Carboxamide Pseudokinase Domain Ligands as Highly Selective Allosteric Inhibitors of Tyrosine Kinase 2 (TYK2)

Identification of N-Methyl Nicotinamide and N-Methyl Pyridazine-3-Carboxamide Pseudokinase Domain Ligands as Highly Selective Allosteric Inhibitors of Tyrosine Kinase 2 (TYK2)

  • J Med Chem. 2019 Oct 24;62(20):8953-8972. doi: 10.1021/acs.jmedchem.9b00443.
Ryan Moslin,  Yanlei Zhang,  Stephen T Wrobleski,  Shuqun Lin,  Michael Mertzman,  Steven Spergel,  John S Tokarski,  Joann Strnad,  Kathleen Gillooly,  Kim W McIntyre,  Adriana Zupa-Fernandez,  Lihong Cheng,  Huadong Sun,  Charu Chaudhry,  Christine Huang,  Celia D'Arienzo,  Elizabeth Heimrich,  Xiaoxia Yang,  Jodi K Muckelbauer,  ChiehYing Chang,  Jeffrey Tredup,  Dawn Mulligan,  Dianlin Xie,  Nelly Aranibar,  Manoj Chiney,  James R Burke,  Louis Lombardo,  Percy H Carter,  David S Weinstein
PMID: 31314518 DOI: 10.1021/acs.jmedchem.9b00443
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.

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