Isocitrate Dehydrogenase Mutation and (R)-2-Hydroxyglutarate: From Basic Discovery to Therapeutics Development

Annu Rev Biochem. 2017 Jun 20;86:305-331. doi: 10.1146/annurev-biochem-061516-044732. Epub 2017 Apr 3.

Abstract

The identification of heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) in subsets of cancers, including secondary glioblastoma, acute myeloid leukemia, intrahepatic cholangiocarcinoma, and chondrosarcomas, led to intense discovery efforts to delineate the mutations' involvement in carcinogenesis and to develop therapeutics, which we review here. The three IDH isoforms (nicotinamide adenine dinucleotide phosphate-dependent IDH1 and IDH2, and nicotinamide adenine dinucleotide-dependent IDH3) contribute to regulating the circuitry of central metabolism. Several biochemical and genetic observations led to the discovery of the neomorphic production of the oncometabolite (R)-2-hydroxyglutarate (2-HG) by mutant IDH1 and IDH2 (mIDH). Heterozygous mutation of IDH1/2 and accumulation of 2-HG cause profound metabolic and epigenetic dysregulation, including inhibition of normal cellular differentiation, leading to disease. Crystallographic structural studies during the development of compounds targeting mIDH demonstrated common allosteric inhibition by distinct chemotypes. Ongoing clinical trials in patients with mIDH advanced hematologic malignancies have demonstrated compelling clinical proof-of-concept, validating the biology and drug discovery approach.

Keywords: allosteric inhibition; cancer therapeutics; metabolism; oncometabolite.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / therapeutic use
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / therapeutic use*
  • Benzeneacetamides / chemical synthesis
  • Benzeneacetamides / therapeutic use
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / therapeutic use
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / metabolism*
  • Drug Discovery
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / therapeutic use
  • Gene Expression
  • Glutarates / analysis
  • Glutarates / metabolism*
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / therapeutic use
  • Isocitrate Dehydrogenase / antagonists & inhibitors*
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / enzymology
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Models, Molecular
  • Mutation
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / therapeutic use
  • Translational Medical Research

Substances

  • 2-(2-(1H-benzo(d)imidazol-1-yl)-N-(3-fluorophenyl)acetamido)-N-cyclopentyl-2-o-tolylacetamide
  • AGI-5198
  • Acetamides
  • Antineoplastic Agents
  • Benzeneacetamides
  • Benzimidazoles
  • Biomarkers, Tumor
  • Enzyme Inhibitors
  • Glutarates
  • Imidazoles
  • Isoenzymes
  • Small Molecule Libraries
  • alpha-hydroxyglutarate
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • IDH1 protein, human