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 language | English |
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Pages (from-to) | 5625-5631 |
Number of pages | 7 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 25 |
Issue number | 23 |
DOIs | |
State | Published - 1 Dec 2015 |
Keywords
- (R)-2-Hydroxyglutarate (R-2HG)
- Isocitrate dehydrogenase-1 (IDH1)
- α-Ketoglutarate (α-KG)
- α-Mangostin