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Discovery of alpha-mangostin as a novel competitive inhibitor against mutant isocitrate dehydrogenase-1
- Authors
- Kim, Hyo-Joon; Fei, Xiang; Cho, Seok-Cheol; Choi, Bu Young; Ahn, Hee-Chul; Lee, Kyeong; Seo, Seung-Yong; Keum, Young-Sam
- Issue Date
- 1-Dec-2015
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- Isocitrate dehydrogenase-1 ( IDH1); alpha-Mangostin; alpha-Ketoglutarate (alpha-KG); (R)-2-Hydroxyglutarate (R-2HG)
- Citation
- BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, v.25, no.23, pp.5625 - 5631
- Journal Title
- BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
- Volume
- 25
- Number
- 23
- Start Page
- 5625
- End Page
- 5631
- ISSN
- 0960-894X
- 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 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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Related Researcher
- Seo, Seung Yong
- Pharmacy (Dept.of Pharmacy)