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

Hyo Joon Kim, Xiang Fei, Seok Cheol Cho, Bu Young Choi, Hee Chul Ahn, Kyeong Lee, Seung Yong Seo, Young Sam Keum

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish
Pages (from-to)5625-5631
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number23
DOIs
StatePublished - 1 Dec 2015

Keywords

  • (R)-2-Hydroxyglutarate (R-2HG)
  • Isocitrate dehydrogenase-1 (IDH1)
  • α-Ketoglutarate (α-KG)
  • α-Mangostin

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