title: Identification and validation of a selective small molecule inhibitor targeting the diacylglycerol acyltransferase 2 activity.
abstract: Diacylglycerol acyltransferase 2 (DGAT2) is one of two distinct DGAT enzymes that catalyze the last step in triacylglycerol (TG) synthesis. Findings from previous studies suggest that inhibition of DGAT2 is a promising strategy for the treatment of hepatic steatosis and insulin resistance. Here, we identified compound 122 as a potent and selective inhibitor of human DGAT2, which appeared to act competitively against oleoyl-CoA in vitro. The selective inhibition of DGAT2 was also confirmed by the reductions in enzymatic activity and de novo TG synthesis in DGAT2-overexpressing HEK293 cells and hepatic cells HepG2. Compound 122, as a newly identified inhibitor of DGAT2, will be useful for the research on DGAT2-related lipid metabolism as well as the development of therapeutic drug for several metabolic diseases.
authors.affiliation: Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon, Chungbuk 363–883, Korea.
authors.forename: Mun Ock
authors.initials: MO
authors.lastname: Kim
authors.forename: Su Ui
authors.initials: SU
authors.lastname: Lee
authors.forename: Hyun-Jun
authors.initials: HJ
authors.lastname: Lee
authors.forename: Kwangman
authors.initials: K
authors.lastname: Choi
authors.forename: Hyeongki
authors.initials: H
authors.lastname: Kim
authors.forename: Sangku
authors.initials: S
authors.lastname: Lee
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
authors.forename: Sunhong
authors.initials: S
authors.lastname: Kim
authors.forename: Jong Soon
authors.initials: JS
authors.lastname: Kang
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: D000818:Animals; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D015394:Molecular Structure; D061987:Sf9 Cells; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D018411:Spodoptera; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; C494881:DGAT1 protein, human; C494885:DGAT2 protein, human; D051048:Diacylglycerol O-Acyltransferase