Discovery of a Novel Class of Diacylglycerol Acyltransferase 2 Inhibitors with a 1<i>H</i>-Pyrrolo[2,3-<i>b</i>]pyridine Core

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  • Kim Mun Ock
    Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology
  • Lee Suui
    Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology
  • Choi Kwangman
    Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology
  • Lee Sangku
    Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology
  • Kim Hyeongki
    Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology Department of Biomolecular Science, University of Science and Technology
  • Kang Hyunju
    Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology
  • Choi Miri
    Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology
  • Kwon Eun Bin
    Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology
  • Kang Myung Ji
    Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology
  • Kim Sunhong
    Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology Department of Biomolecular Science, University of Science and Technology
  • Lee Hyun-Jun
    Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology
  • Lee Hyun Sun
    Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology
  • Kwak Young-Shin
    College of Pharmacy, Korea University
  • Cho Sungchan
    Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology Department of Biomolecular Science, University of Science and Technology

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  • 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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