157977-55-4Relevant articles and documents
Structure-Activity Relationship Studies of α-Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family
Zhou, Juan,Mock, Elliot D.,Al Ayed, Karol,Di, Xinyu,Kantae, Vasudev,Burggraaff, Lindsey,Stevens, Anna F.,Martella, Andrea,Mohr, Florian,Jiang, Ming,Van Der Wel, Tom,Wendel, Tiemen J.,Ofman, Tim P.,Tran, Yvonne,De Koster, Nicky,Van Westen, Gerard J.P.,Hankemeier, Thomas,Van Der Stelt, Mario
, p. 9340 - 9359 (2020/10/19)
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.
