Discovery of a novel class of diacylglycerol acyltransferase 2 inhibitors with a 1H-pyrrolo[2,3-b]pyridine core.
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| 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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| Authors | Mun Ock Kim, Suui Lee, Kwangman Choi, Sangku Lee, Hyeongki Kim, Hyunju Kang, Miri Choi, Eun Bin Kwon, Myung Ji Kang, Sunhong Kim, Hyun-Jun Lee, Hyun Sun Lee, Young-Shin Kwak, Sungchan Cho |
| Journal | Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 37 Issue 10 Pg. 1655-60 ( 2014) ISSN: 1347-5215 [Electronic] Japan |
| PMID | 25099343 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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