| Literature DB >> 26508549 |
Hyo-Joon Kim1, Xiang Fei2, Seok-Cheol Cho3, Bu Young Choi3, Hee-Chul Ahn1, Kyeong Lee1, Seung-Yong Seo2, Young-Sam Keum4.
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.Entities:
Keywords: (R)-2-Hydroxyglutarate (R-2HG); Isocitrate dehydrogenase-1 (IDH1); α-Ketoglutarate (α-KG); α-Mangostin
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Year: 2015 PMID： 26508549 DOI： 10.1016/j.bmcl.2015.10.034
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823