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

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

  • Bioorg Med Chem Lett. 2015 Dec 1;25(23):5625-31. doi: 10.1016/j.bmcl.2015.10.034.
Hyo-Joon Kim 1,  Xiang Fei 2,  Seok-Cheol Cho 3,  Bu Young Choi 3,  Hee-Chul Ahn 1,  Kyeong Lee 1,  Seung-Yong Seo 2,  Young-Sam Keum 4
Affiliations

Affiliations

  • 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.
PMID: 26508549 DOI: 10.1016/j.bmcl.2015.10.034
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.

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