title: Discovery of a novel class of diacylglycerol acyltransferase 2 inhibitors with a 1H-pyrrolo[2,3-b]pyridine core.
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.
authors.affiliation: Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology.
authors.forename: Mun Ock
authors.initials: MO
authors.lastname: Kim
authors.forename: Suui
authors.initials: S
authors.lastname: Lee
authors.forename: Kwangman
authors.initials: K
authors.lastname: Choi
authors.forename: Sangku
authors.initials: S
authors.lastname: Lee
authors.forename: Hyeongki
authors.initials: H
authors.lastname: Kim
authors.forename: Hyunju
authors.initials: H
authors.lastname: Kang
authors.forename: Miri
authors.initials: M
authors.lastname: Choi
authors.forename: Eun Bin
authors.initials: EB
authors.lastname: Kwon
authors.forename: Myung Ji
authors.initials: MJ
authors.lastname: Kang
authors.forename: Sunhong
authors.initials: S
authors.lastname: Kim
authors.forename: Hyun-Jun
authors.initials: HJ
authors.lastname: Lee
authors.forename: Hyun Sun
authors.initials: HS
authors.lastname: Lee
authors.forename: Young-Shin
authors.initials: YS
authors.lastname: Kwak
authors.forename: Sungchan
authors.initials: S
authors.lastname: Cho
mesh_terms: D041721:3T3-L1 Cells; D000085:Acetates / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C413877:1H-pyrrolo(2,3-b)pyridine-3-acetic acid; D000085:Acetates; D011725:Pyridines; C516957:DGAT2 protein, mouse; D051048:Diacylglycerol O-Acyltransferase