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

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.