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

초록

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 alpha-mangostin as a novel selective inhibitor of mutant IDH1 (IDH1-R132H). We have observed that alpha-mangostin competitively inhibits the binding of alpha-ketoglutarate (alpha-KG) to IDH1-R132H. The structure-relationship study reveals that alpha-mangostin exhibits the strongest core inhibitor structure. Finally, we have observed that alpha-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 alpha-KG-dependent DNA hydroxylases and histone H3 lysine demethylases. Collectively, we provide evidence that alpha-mangostin selectively inhibits IDH1-R132H. (C) 2015 Elsevier Ltd. All rights reserved.

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