A Brain Penetrant Mutant IDH1 Inhibitor Provides In Vivo Survival Benefit

Sci Rep. 2017 Oct 23;7(1):13853. doi: 10.1038/s41598-017-14065-w.


Mutations in IDH1 are highly prevalent in human glioma. First line treatment is radiotherapy, which many patients often forego to avoid treatment-associated morbidities. The high prevalence of IDH1 mutations in glioma highlights the need for brain-penetrant IDH1 mutant-selective inhibitors as an alternative therapeutic option. Here, we have explored the utility of such an inhibitor in IDH1 mutant patient-derived models to assess the potential therapeutic benefits associated with intracranial 2-HG inhibition. Treatment of mutant IDH1 cell line models led to a decrease in intracellular 2-HG levels both in vitro and in vivo. Interestingly, inhibition of 2-HG production had no effect on in vitro IDH1 mutant glioma cell proliferation. In contrast, IDH1 mutant-selective inhibitors provided considerable survival benefit in vivo. However, even with near complete inhibition of intratumoral 2-HG production, not all mutant glioma models responded to treatment. The results suggest that disruption of 2-HG production with brain-penetrant inhibitors in IDH1 mutant gliomas may have substantial patient benefit.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / genetics
  • Brain Neoplasms / mortality*
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Gene Expression Profiling
  • Glioma / drug therapy
  • Glioma / genetics
  • Glioma / mortality*
  • Glutarates / metabolism*
  • Humans
  • Isocitrate Dehydrogenase / antagonists & inhibitors*
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism
  • Mice, Inbred C57BL
  • Mice, SCID
  • Mutant Proteins / antagonists & inhibitors*
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Mutation*
  • Survival Rate
  • Xenograft Model Antitumor Assays


  • Enzyme Inhibitors
  • Glutarates
  • Mutant Proteins
  • alpha-hydroxyglutarate
  • Isocitrate Dehydrogenase
  • IDH1 protein, human