TARGETING gliomas through dual mutant IDH1/2 – BET inhibition


The rationale (IDH mutant targeting)

  • Low-level of 2-HG under normal homeostasis is rapidly cleared via conversion to αKG by chirality-specific dehydrogenases (D-2HGDH or L-2HGDH).
  • Mutant IDH1/2 leads to enhanced production of 2HG that cannot be converted back to α-KG.
  • 2HG is the oncometabolite that inhibits hypoxia induced factor (HIF) as well as αKG dependent dioxygenase leading to genome wide epigenetic changes.