Discovery of α-mangostin as a novel competitive inhibitor against mutant isocitrate dehydrogenase-1.
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.
College of Pharmacy, Dongguk University, Goyang, Gyeonggi-do 410-820, Republic of Korea.
Hyo-Joon
HJ
Kim
College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-779, Republic of Korea.
Xiang
X
Fei
Department of Pharmaceutical Science and Engineering, Seowon University, Cheongju, Chungbuk 361-742, Republic of Korea.
Seok-Cheol
SC
Cho
Department of Pharmaceutical Science and Engineering, Seowon University, Cheongju, Chungbuk 361-742, Republic of Korea.
Bu Young
BY
Choi
College of Pharmacy, Dongguk University, Goyang, Gyeonggi-do 410-820, Republic of Korea.
Hee-Chul
HC
Ahn
College of Pharmacy, Dongguk University, Goyang, Gyeonggi-do 410-820, Republic of Korea.
Kyeong
K
Lee
College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-779, Republic of Korea.
Seung-Yong
SY
Seo
College of Pharmacy, Dongguk University, Goyang, Gyeonggi-do 410-820, Republic of Korea. Electronic address: keum03@dongguk.edu.
Young-Sam
YS
Keum
D001667:Binding, Competitive; D055808:Drug Discovery; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D061986:MCF-7 Cells; D015394:Molecular Structure; D009154:Mutation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000737:chemistry* / Q000494:pharmacology
D011994:Recombinant Proteins; D044004:Xanthones; D007521:Isocitrate Dehydrogenase; C021053:mangostin
(R)-2-Hydroxyglutarate (R-2HG); Isocitrate dehydrogenase-1 (IDH1); α-Ketoglutarate (α-KG); α-Mangostin