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ID: ALA3632508

Journal: Bioorg Med Chem Lett

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

Authors: Kim HJ, Fei X, Cho SC, Choi BY, Ahn HC, Lee K, Seo SY, Keum YS.

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.

CiteXplore: 26508549

DOI: 10.1016/j.bmcl.2015.10.034