I-8, a Novel Inhibitor of Mutant IDH1, Inhibits Cancer Progression in Vitro and in Vivo

Eur J Pharm Sci. 2019 Dec 1;140:105072. doi: 10.1016/j.ejps.2019.105072. Epub 2019 Sep 10.


Isocitrate dehydrogenase 1 mutations have been discovered in an array of hematologic malignancies and solid tumors. These mutations could cause the production of high levels of 2-hydroxyglutarate, which in turn implicated in epigenetic changes and impaired cell differentiation. Here, we described the characterization of compound I-8, a novel mutant IDH1 inhibitor, both in vitro and in vivo. Compound I-8 specifically inhibited 2-HG production, reduced histone methylation levels, induced differentiation and depleted stem characteristics in engineered and endogenous IDH1 mutant cells. In addition, oral administration of I-8 also significantly suppressed 2-HG production and histone methylation with dose of 150 mg/kg. And I-8 treatment also could induce differentiation and attenuate stem characteristics in tumor tissue. Together, these studies indicated that compound I-8 has clinical potential in tumor therapies as a effective mutant IDH1 inhibitor, and provided scientific guidance for the development of mutant IDH1 inhibitor in the future.

Keywords: 2-Hydroxyglutarate; Compound I-8; Differentiation; Histone methylation; Isocitrate dehydrogenase 1; Mutant IDH1 inhibitor.

MeSH terms

  • Actins / metabolism
  • Animals
  • Antineoplastic Agents / chemistry*
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry*
  • Epigenesis, Genetic
  • Glutarates / metabolism
  • Histones / metabolism
  • Humans
  • Isocitrate Dehydrogenase / antagonists & inhibitors*
  • Isocitrate Dehydrogenase / genetics
  • Methylation / drug effects
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Docking Simulation
  • Mutation
  • Protein Binding
  • Protein Conformation


  • Actins
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Glutarates
  • Histones
  • alpha-hydroxyglutarate
  • Isocitrate Dehydrogenase