StructureActivity Relationship Studies of Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family [component]

The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca 2+ -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
more » ... id levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure−activity relationships of the αketoamide 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.
doi:10.1021/acs.jmedchem.0c00522.s002 fatcat:asoqhtblafe5dnfbm5j6yeeslu