Rational design, synthesis and biological profiling of new KDM4C inhibitors

Bioorg Med Chem. 2020 Jan 1;28(1):115128. doi: 10.1016/j.bmc.2019.115128. Epub 2019 Nov 8.

Abstract

The human histone demethylases of the KDM4 family have been related to diseases such as prostate and breast cancer. Majority of currently known inhibitors suffer from the low permeability and low selectivity between the enzyme isoforms. In this study, toxoflavin motif was used to design and synthesize new KDM4C inhibitors with improved biological activity and in vitro ADME properties. Inhibitors displayed good passive cellular permeability and metabolic stability. However, diminishing of redox liability and consequently non-specific influence on cell viability still remains a challenge.

Keywords: Computational chemistry; Drug design; Epigenetics; Inhibitor; KDM4C enzyme.

MeSH terms

  • A549 Cells
  • Animals
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Madin Darby Canine Kidney Cells
  • Mice
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Quantum Theory
  • Structure-Activity Relationship
  • Triazines / chemical synthesis
  • Triazines / chemistry
  • Triazines / pharmacology*

Substances

  • Enzyme Inhibitors
  • KDM4C protein, human
  • Pyrimidinones
  • Triazines
  • toxoflavin
  • Jumonji Domain-Containing Histone Demethylases