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Bioorg Med Chem Lett. 2015 Dec 1;25(23):5625-31. doi: 10.1016/j.bmcl.2015.10.034. Epub 2015 Oct 23.

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

Author information

1
College of Pharmacy, Dongguk University, Goyang, Gyeonggi-do 410-820, Republic of Korea.
2
College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-779, Republic of Korea.
3
Department of Pharmaceutical Science and Engineering, Seowon University, Cheongju, Chungbuk 361-742, Republic of Korea.
4
College of Pharmacy, Dongguk University, Goyang, Gyeonggi-do 410-820, Republic of Korea. Electronic address: keum03@dongguk.edu.

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.

KEYWORDS:

(R)-2-Hydroxyglutarate (R-2HG); Isocitrate dehydrogenase-1 (IDH1); α-Ketoglutarate (α-KG); α-Mangostin

PMID:
26508549
DOI:
10.1016/j.bmcl.2015.10.034
[Indexed for MEDLINE]

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