Structure-based screening of tetrazolylhydrazide inhibitors vs. KDM4 histone demethylases


  • P.H. Malecki
  • N. Rueger
  • M. Roatsch
  • O. Krylova
  • A. Link
  • M. Jung
  • U. Heinemann
  • M.S. Weiss


  • ChemMedChem


  • ChemMedChem


  • Human histone demethylases are known to play an important role in the development of several tumor types. Consequently, they have emerged as important medical targets for the treatment of human cancer. Herein, we report the structural studies of tetrazolylhydrazide inhibitors reported as a new scaffold for a certain class of histone demethylases, the JmjC proteins. We structurally describe a series of compounds and examine their respective binding modes to the KDM4D protein, which served us as a high-resolution model representing the KDM4 subfamily in crystallographic studies. Similar to previously reported inhibitors, the herein described compounds are competitors to the natural KDM4 co-factor 2-oxoglutarate (2OG). The tetrazolylhydrazide scaffold fills an important gap in KDM4 inhibition and newly described detailed interactions of inhibitors moieties pave the way to developing compounds with high target-binding affinity and increased membrane permeability at the same time.