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Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation

Fang Wang1, Jeremy Travins, Byron DeLaBarre

  • 1Agios Pharmaceuticals, Cambridge, MA 02139-4169, USA.

Science (New York, N.Y.)
|April 6, 2013
PubMed

Insights

A novel small molecule, AGI-6780, selectively inhibits mutant isocitrate dehydrogenase 2 (IDH2/R140Q), a key driver in certain cancers. This targeted inhibition shows potential for differentiation therapy in cancer treatment.

Area of Science:

  • Oncology
  • Biochemistry
  • Molecular Biology

Background:

  • Somatic mutations in isocitrate dehydrogenases 1 and 2 (IDH1/IDH2) are prevalent in human cancers.
  • These mutations lead to a gain-of-function, causing the accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG).

Purpose of the Study:

  • To develop and characterize a small molecule inhibitor targeting the tumor-associated mutant IDH2/R140Q.
  • To investigate the therapeutic potential of inhibiting mutant IDH2/R140Q as a cancer differentiation therapy.

Main Methods:

  • Development of a small molecule inhibitor, AGI-6780.
  • Crystal structure analysis of AGI-6780 complexed with IDH2/R140Q.
  • Steady-state enzymology analysis.
  • In vitro differentiation assays using TF-1 erythroleukemia and acute myelogenous leukemia cells.

Main Results:

  • AGI-6780 potently and selectively inhibits mutant IDH2/R140Q.
  • Crystal structure revealed allosteric binding of AGI-6780 at the dimer interface.
  • Enzymology data indicated allosteric inhibition and slow-tight binding kinetics.
  • AGI-6780 treatment induced cellular differentiation in leukemia cell lines.

Conclusions:

  • AGI-6780 is a potent and selective allosteric inhibitor of mutant IDH2/R140Q.
  • The findings provide proof-of-concept for targeting mutant IDH2/R140Q with small molecule inhibitors.
  • Inhibitors of mutant IDH2/R140Q may represent a novel differentiation therapy for cancers harboring these mutations.

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