Discovery of a Novel Class of Diacylglycerol Acyltransferase 2 Inhibitors with a 1H-Pyrrolo[2,3-b]pyridine Core
- Authors
- Kim, Mun Ock; Lee, Suui; Choi, Kwangman; Lee, Sangku; Kim, Hyeongki; Kang, Hyunju; Choi, Miri; Kwon, Eun Bin; Kang, Myung Ji; Kim, Sunhong; Lee, Hyun-Jun; Lee, Hyun Sun; Kwak, Young-Shin; Cho, Sungchan
- Issue Date
- 10월-2014
- Publisher
- PHARMACEUTICAL SOC JAPAN
- Keywords
- metabolic disease; triacylglycerol; diacylglycerol acyltransferase 2 (DGAT2); small molecule inhibitor
- Citation
- BIOLOGICAL & PHARMACEUTICAL BULLETIN, v.37, no.10, pp.1655 - 1660
- Indexed
- SCIE
SCOPUS
- Journal Title
- BIOLOGICAL & PHARMACEUTICAL BULLETIN
- Volume
- 37
- Number
- 10
- Start Page
- 1655
- End Page
- 1660
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/97345
- DOI
- 10.1248/bpb.b14-00447
- ISSN
- 0918-6158
- Abstract
- Diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step in triacylglycerol (TG) synthesis, is a key enzyme associated with hepatic steatosis and insulin resistance. Here, using an in vitro screen of 20000 molecules, we identified a class of compounds with a substituted 1H-pyrrolo[2,3-b]pyridine core which proved to be potent and selective inhibitors of human DGAT2. Of these compounds, H2-003 and -005 exhibited a considerable reduction in TG biosynthesis in HepG2 hepatic cells and 3T3-L1 preadipose cells. These compounds exert DGAT2-specific-inhibitory activity, which was further confirmed in DGAT2- or DGAT1-overexpressing HEK293 cells. In addition, these compounds almost completely abolished lipid droplet formation in 3T3-L1 cells when co-treated with a DGAT1 inhibitor, which was not attained using either a DGAT2 or DGAT1 inhibitor alone. Collectively, we identified two DGAT2 inhibitors, H2-003 and -005. These compounds will aid in DGAT2-related lipid metabolism research as well as in therapeutic development for the treatment of metabolic diseases associated with excessive TG.
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