Discovery of Tyk2 inhibitors via the virtual site-directed fragment-based drug design

Bioorg Med Chem Lett. 2015 Sep 15;25(18):3947-52. doi: 10.1016/j.bmcl.2015.07.037. Epub 2015 Jul 21.

Abstract

In this study, we synthesized compound 12 with potent Tyk2 inhibitory activity from FBDD study and carried out a cell-based assay for Tyk2/STAT3 signaling activation upon IFNα5 stimulation. Compound 12 completely suppressed the IFNα5-mediated Tyk2/STAT3 signaling pathway as well as the basal levels of pSTAT3. Stimulation with IFNα/β leads to the tyrosine phosphorylation of the JAK1 and Tyk2 receptor-associated kinases with subsequent STATs activation, transmitting signals from the cell surface receptor to the nucleus. In conclusion, the potency of compound 12 to interrupt the signal transmission of Tyk2/STAT3 appeared to be equivalent or superior to that of the reference compound.

Keywords: FBDD; Inhibitor; STATs activation; Tyk2; Water-ring analysis.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Molecular Conformation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • TYK2 Kinase / antagonists & inhibitors*
  • TYK2 Kinase / metabolism

Substances

  • Protein Kinase Inhibitors
  • TYK2 Kinase
  • TYK2 protein, human