Discovery of α-mangostin as a novel competitive inhibitor against mutant isocitrate dehydrogenase-1

Bioorg Med Chem Lett. 2015 Dec 1;25(23):5625-31. doi: 10.1016/j.bmcl.2015.10.034. Epub 2015 Oct 23.

Abstract

Somatic heterozygous mutations of isocitrate dehydrogenase-1 (IDH1) are abundantly found in several types of cancer and strongly implicate altered metabolism in carcinogenesis. In the present study, we have identified α-mangostin as a novel selective inhibitor of mutant IDH1 (IDH1-R132H). We have observed that α-mangostin competitively inhibits the binding of α-ketoglutarate (α-KG) to IDH1-R132H. The structure-relationship study reveals that α-mangostin exhibits the strongest core inhibitor structure. Finally, we have observed that α-mangostin selectively promotes demethylation of 5-methylcytosine (5mC) and histone H3 trimethylated lysine residues in IDH1 (+/R132H) MCF10A cells, presumably via restoring the activity of cellular α-KG-dependent DNA hydroxylases and histone H3 lysine demethylases. Collectively, we provide evidence that α-mangostin selectively inhibits IDH1-R132H.

Keywords: (R)-2-Hydroxyglutarate (R-2HG); Isocitrate dehydrogenase-1 (IDH1); α-Ketoglutarate (α-KG); α-Mangostin.

MeSH terms

  • Binding, Competitive
  • Drug Discovery*
  • Humans
  • Isocitrate Dehydrogenase / antagonists & inhibitors*
  • Isocitrate Dehydrogenase / genetics
  • MCF-7 Cells
  • Molecular Structure
  • Mutation
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Structure-Activity Relationship
  • Xanthones / chemistry*
  • Xanthones / pharmacology

Substances

  • Recombinant Proteins
  • Xanthones
  • Isocitrate Dehydrogenase
  • mangostin