Identification of imidazo[1,2- b ]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling

作者：Ryan Moslin, Daniel S. Gardner, Joseph B. Santella, Y. Zhang, John V. Duncia, C. Liu, Jian‐Xian Lin, John S. Tokarski, Joann Strnad, Donna L. Pedicord, J. Chen, Yuval Blat, Adriana Zupa-Fernandez, Lihong Cheng, Hongzhi Sun, Charu Chaudhry, Christine Huang, Celia D’Arienzo, John S. Sack, J.K. Muckelbauer, ChiehYing Y. Chang, Jeffrey Tredup, Dan Xie, Nelly Aranı́bar, James R. Burke, P. H. Carter, David S. Weinstein · 发表于：MedChemComm · 年份：2016 · DOI：10.1039/c6md00560h · 被引用次数：51 · 研究领域：Cytokine Signaling Pathways and Interactions、Myeloproliferative Neoplasms: Diagnosis and Treatment

, which provided encouraging systemic exposures after oral dosing in mice. Phosphodiesterase 4 (PDE4) was identified as an off-target and potential liability of the IZP ligands, and selectivity for TYK2 JH2 over this enzyme was obtained by elaborating along selectivity vectors determined from analyses of X-ray co-crystal structures of representative ligands of the IZP class bound to both proteins.