Structure-based development of novel substrate-type G9a inhibitors as epigenetic modulators for sickle cell disease treatment

Bioorg Med Chem Lett. 2024 Sep 15:110:129856. doi: 10.1016/j.bmcl.2024.129856. Epub 2024 Jun 22.

Abstract

The discovery and development of structurally distinct lysine methyltransferase G9a inhibitors have been the subject of intense research in epigenetics. Structure-based optimization was conducted, starting with the previously reported seed compound 7a and lead to the identification of a highly potent G9a inhibitor, compound 7i (IC50 = 0.024 μM). X-ray crystallography for the ligand-protein interaction and kinetics study, along with surface plasmon resonance (SPR) analysis, revealed that compound 7i interacts with G9a in a unique binding mode. In addition, compound 7i caused attenuation of cellular H3K9me2 levels and induction of γ-globin mRNA expression in HUDEP-2 cells in a dose-dependent manner.

Keywords: G9a inhibitor; Sickle cell disease; Structure-based optimization; Surface plasmon resonance analysis; X-ray crystallography.

MeSH terms

  • Anemia, Sickle Cell* / drug therapy
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Epigenesis, Genetic* / drug effects
  • Histocompatibility Antigens / metabolism
  • Histone-Lysine N-Methyltransferase* / antagonists & inhibitors
  • Histone-Lysine N-Methyltransferase* / metabolism
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Histone-Lysine N-Methyltransferase
  • EHMT2 protein, human
  • Enzyme Inhibitors
  • Histocompatibility Antigens