Drug Discovery Researches on Modulators of Lysine-Modifying Enzymes Based on Strategic Chemistry Approaches

Chem Pharm Bull (Tokyo). 2020;68(1):34-45. doi: 10.1248/cpb.c19-00741.


Enzymatic and post-translational modifications (PTMs) such as ubiquitination, acetylation, and methylation occur at lysine residues. The PTMs play critical roles in the regulation of the protein functions, and thus, various cellular processes. In addition, aberrations of the PTMs are associated with various diseases, such as cancer and neurodegenerative disorders. Therefore, we hypothesized that modulation of the PTMs and normalization of the PTM abnormalities could be useful as methods to control various cellular mechanisms and as a therapeutic strategy, respectively. To modulate the PTMs, we have focused on lysine-modifying enzymes and have pursued drug discovery researches on ubiquitination inducers, lysine deacetylase (KDAC) inhibitors, and lysine demethylase (KDM) inhibitors. For the identification of the modulators, we have used not only conventional drug design, such as structure-based drug design (SBDD) and ligand-based drug design (LBDD), but also "strategic chemistry approaches," such as drug design based on enzyme catalytic mechanism. As a result, we have identified several modulators which have pharmacological effects in animal models or in cellular studies. In this review, focusing on the drug design based on enzyme catalytic mechanism, our drug discovery researches have been discussed.

Keywords: deacetylase; demethylase; enzyme inhibitor; protein knockdown; proteolysis-targeting chimera (PROTAC); ubiquitin ligase.

Publication types

  • Review

MeSH terms

  • Carboxy-Lyases / antagonists & inhibitors
  • Carboxy-Lyases / metabolism*
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Histone Demethylases / antagonists & inhibitors
  • Histone Demethylases / metabolism*
  • Humans
  • Lysine / chemistry*
  • Lysine / metabolism
  • Protein Processing, Post-Translational
  • Ubiquitin-Conjugating Enzymes / antagonists & inhibitors
  • Ubiquitin-Conjugating Enzymes / metabolism


  • Enzyme Inhibitors
  • Histone Demethylases
  • Ubiquitin-Conjugating Enzymes
  • Carboxy-Lyases
  • lysine decarboxylase
  • Lysine