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

Hyo Joon Kim; Xiang Fei; Seok Cheol Cho; Bu Young Choi; Hee Chul Ahn; Kyeong Lee; Seung Yong Seo; Young Sam Keum

doi:10.1016/j.bmcl.2015.10.034

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

Hyo Joon Kim
, Xiang Fei
, Seok Cheol Cho
, Bu Young Choi
, Hee Chul Ahn
, Kyeong Lee
, Seung Yong Seo
, Young Sam Keum

Department of Pharmacy

Dongguk University
Gachon University
Seowon University

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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.

Original language	English
Pages (from-to)	5625-5631
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2015.10.034
State	Published - 1 Dec 2015

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

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10.1016/j.bmcl.2015.10.034

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title = "Discovery of α-mangostin as a novel competitive inhibitor against mutant isocitrate dehydrogenase-1",

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",

author = "Kim, \{Hyo Joon\} and Xiang Fei and Cho, \{Seok Cheol\} and Choi, \{Bu Young\} and Ahn, \{Hee Chul\} and Kyeong Lee and Seo, \{Seung Yong\} and Keum, \{Young Sam\}",

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doi = "10.1016/j.bmcl.2015.10.034",

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T1 - Discovery of α-mangostin as a novel competitive inhibitor against mutant isocitrate dehydrogenase-1

AU - Kim, Hyo Joon

AU - Fei, Xiang

AU - Cho, Seok Cheol

AU - Choi, Bu Young

AU - Ahn, Hee Chul

AU - Lee, Kyeong

AU - Seo, Seung Yong

AU - Keum, Young Sam

PY - 2015/12/1

Y1 - 2015/12/1

N2 - 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.

AB - 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.

KW - (R)-2-Hydroxyglutarate (R-2HG)

KW - Isocitrate dehydrogenase-1 (IDH1)

KW - α-Ketoglutarate (α-KG)

KW - α-Mangostin

UR - https://www.scopus.com/pages/publications/84946557630

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AN - SCOPUS:84946557630

SN - 0960-894X

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 23

ER -

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

Abstract

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Keywords

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