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Structure-Activity Relationship Studies of α-Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family.

  • Zhou, Juan1
  • Mock, Elliot D1
  • Al Ayed, Karol1
  • Di, Xinyu2
  • Kantae, Vasudev2
  • Burggraaff, Lindsey3
  • Stevens, Anna F1
  • Martella, Andrea1
  • Mohr, Florian1
  • Jiang, Ming1
  • van der Wel, Tom1
  • Wendel, Tiemen J1
  • Ofman, Tim P1
  • Tran, Yvonne1
  • de Koster, Nicky1
  • van Westen, Gerard J P3
  • Hankemeier, Thomas2
  • van der Stelt, Mario1
  • 1 Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University & Oncode Institute, 2300 RA Leiden, The Netherlands. , (Netherlands)
  • 2 Department of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands. , (Netherlands)
  • 3 Department of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands. , (Netherlands)
Published Article
Journal of Medicinal Chemistry
American Chemical Society
Publication Date
Aug 13, 2020
DOI: 10.1021/acs.jmedchem.0c00522
PMID: 32787138


The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca2+-independent production of N-acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive N-acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified α-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure-activity relationships of the α-ketoamide series using activity-based protein profiling. This led to the identification of LEI-301, a nanomolar potent inhibitor for the PLAAT family members. LEI-301 reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. Collectively, LEI-301 may help to dissect the physiological role of the PLAATs.

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