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

Abstract

The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca²⁺-independent production of <i>N</i>-acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive <i>N</i>-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 <b>LEI-301</b>, a nanomolar potent inhibitor for the PLAAT family members. <b>LEI-301</b> reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. Collectively, <b>LEI-301</b> may help to dissect the physiological role of the PLAATs.