Discovery of a novel class of diacylglycerol acyltransferase 2 inhibitors with a 1H-Pyrrolo[2,3-b]pyridine core = DGAT2의 신규 억제물질 발굴

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Title
Discovery of a novel class of diacylglycerol acyltransferase 2 inhibitors with a 1H-Pyrrolo[2,3-b]pyridine core = DGAT2의 신규 억제물질 발굴
Author(s)
Mun-Ock KimSu Ui Lee; Kwang Man Choi; Sangku Lee; Hyeong Ki Kim; Hyun Ju Kang; Miri Choi; Eun Bin Kwon; Myung Ji Kang; Sun Hong Kim; Hyun-Jun Lee; Hyun Sun Lee; Y S Kwak; Sungchan Cho
Bibliographic Citation
Biological & Pharmaceutical Bulletin, vol. 37, no. 10, pp. 1655-1660
Publication Year
2014
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. --------------------------------------------------------------------------------
Keyword
Diacylglycerol acyltransferase 2 (DGAT2)Metabolic diseaseSmall molecule inhibitorTriacylglycerol
ISSN
0918-6158
Publisher
Pharmaceutical Soc Japan
DOI
http://dx.doi.org/10.1248/bpb.b14-00447
Type
Article
Appears in Collections:
Ochang Branch Institute > Natural Product Research Center > 1. Journal Articles
Ochang Branch Institute > Chemical Biology Research Center > 1. Journal Articles
Ochang Branch Institute > Nucleic Acid Therapeutics Research Center > 1. Journal Articles
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