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Related Experiment Videos

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

Lenny Dang1, Shin-San Michael Su1

  • 1Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139; email: Lenny.Dang@agios.com , Shinsan.Su@agios.com.

Annual Review of Biochemistry
|April 5, 2017
PubMed
Summary

Mutations in isocitrate dehydrogenase (IDH) enzymes drive cancer by producing an oncometabolite, (R)-2-hydroxyglutarate (2-HG). This disrupts cellular metabolism and epigenetics, leading to diseases like glioblastoma and leukemia.

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Preclinical Drug Metabolism, Pharmacokinetic, and Pharmacodynamic Profiles of Ivosidenib, an Inhibitor of Mutant Isocitrate Dehydrogenase 1 for Treatment of Isocitrate Dehydrogenase 1-Mutant Malignancies.

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Area of Science:

  • Biochemistry
  • Oncology
  • Metabolic pathways

Background:

  • Heterozygous mutations in isocitrate dehydrogenase (IDH) are found in various cancers.
  • IDH enzymes (IDH1, IDH2, IDH3) are crucial for central metabolism.
  • Mutant IDH (mIDH) leads to the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG).

Purpose of the Study:

  • To review the role of IDH mutations in carcinogenesis.
  • To explore the development of therapeutics targeting mIDH.
  • To understand the metabolic and epigenetic consequences of 2-HG accumulation.

Main Methods:

  • Biochemical and genetic analyses to identify oncometabolite production.
  • Crystallographic studies to understand drug-target interactions.
  • Review of ongoing clinical trials for mIDH-mutated cancers.
Keywords:
allosteric inhibitioncancer therapeuticsmetabolismoncometabolite

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Main Results:

  • IDH mutations lead to neomorphic production of 2-HG.
  • Accumulation of 2-HG causes metabolic and epigenetic dysregulation.
  • Targeting mIDH with small molecules shows promise in clinical trials.

Conclusions:

  • IDH mutations and 2-HG accumulation are key drivers in specific cancers.
  • Targeting mIDH represents a validated therapeutic strategy.
  • Clinical trials demonstrate proof-of-concept for mIDH-targeted therapies.