An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells

Science. 2013 May 3;340(6132):626-30. doi: 10.1126/science.1236062. Epub 2013 Apr 4.

Abstract

The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1), which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant--but not IDH1-wild-type--glioma cells without appreciable changes in genome-wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzeneacetamides / administration & dosage
  • Benzeneacetamides / pharmacology*
  • Benzeneacetamides / toxicity
  • Cell Differentiation* / drug effects
  • Cell Transformation, Neoplastic
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / toxicity
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioma / drug therapy
  • Glioma / enzymology*
  • Glioma / genetics
  • Glioma / pathology*
  • Glutarates / metabolism
  • Histones / metabolism
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacology*
  • Imidazoles / toxicity
  • Isocitrate Dehydrogenase / antagonists & inhibitors*
  • Isocitrate Dehydrogenase / chemistry
  • Isocitrate Dehydrogenase / genetics*
  • Isocitrate Dehydrogenase / metabolism
  • Methylation
  • Mice
  • Mice, SCID
  • Mutant Proteins / antagonists & inhibitors
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Protein Multimerization
  • RNA Interference
  • Xenograft Model Antitumor Assays

Substances

  • AGI-5198
  • Benzeneacetamides
  • Enzyme Inhibitors
  • Glutarates
  • Histones
  • Imidazoles
  • Mutant Proteins
  • alpha-hydroxyglutarate
  • Isocitrate Dehydrogenase
  • IDH1 protein, human

Associated data

  • GEO/GSE45200