Identification and characterization of a novel mutant isocitrate dehydrogenase 1 inhibitor for glioma treatment

Biochem Biophys Res Commun. 2021 Apr 30:551:38-45. doi: 10.1016/j.bbrc.2021.02.112. Epub 2021 Mar 11.

Abstract

Isocitrate dehydrogenase 1 (IDH1) mutant R132H, promoting the oncometabolite D-2-hydroxyglutarate (D2HG), is a driver mutation and an emerging therapeutic target in glioma. This study identified a novel mutant IDH1 inhibitor, WM17, by virtual screening and enzymatic confirmation. It could bind to and increase mutant IDH1 protein's thermostability in both endogenous heterozygous cells and exogenous overexpressed cells. Consequently, WM17 reversed the accumulation of D2HG and histone hypermethylation in IDH1 mutated cells. Finally, we concluded that WM17 significantly inhibited cell migration in IDH1 mutated glioma cells, although it has no apparent effect on cell proliferation. Further studies are guaranteed toward the development of WM17 as a therapeutic agent for IDH1 mutated glioma.

Keywords: D-2-hydroxyglutarate; Glioma; Mutant IDH1; WM17.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzeneacetamides / pharmacology
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Enzyme Stability / drug effects
  • Glioma / drug therapy*
  • Glioma / enzymology
  • Glioma / genetics
  • Glioma / pathology
  • Histones / metabolism
  • Humans
  • Imidazoles / pharmacology
  • Isocitrate Dehydrogenase / antagonists & inhibitors*
  • Isocitrate Dehydrogenase / genetics*
  • Methylation / drug effects
  • Models, Molecular
  • Molecular Targeted Therapy
  • Mutant Proteins / antagonists & inhibitors*
  • Mutant Proteins / genetics
  • Mutation*
  • Protein Binding

Substances

  • AGI-5198
  • Benzeneacetamides
  • Cadherins
  • Histones
  • Imidazoles
  • Mutant Proteins
  • Isocitrate Dehydrogenase
  • IDH1 protein, human