KT109 is a potent and selective inhibitor of Diacylglycerol lipase DAGLβ. Diacylglycerol lipases DAGLα and DAGLβ are serine hydrolases that biosynthesize the endocannabinoid 2-arachidonoylglycerol (2-AG). A lack of selective inhibitors has hampered study of these lipases. KT109 is a potent and selective DAGLβ inhibitor with an IC50 of 42 nM, ~60-fold selectivity for DAGLβ over DAGLα, and negligible activity against FAAH, MGLL and ABHD11, other key enzymes involved in endocannabinoid signaling. KT109 shows some inhibitory activity against PLA2G7 (IC50 = 1 μM) but no inhibitory activity against cytosolic phospholipase A2 (cPLA2 or PLA2G4A). The main off target inhibition against ABHD6 (IC50 = 16 nM) can be controlled for by use of the related compound, KT195, a potent (IC50 = 10 nM) and selective ABHD6 inhibitor with negligible activity against DAGLβ. KT109 disrupts the lipid network involved in macrophage inflammatory responses, lowering 2-AG, as well as arachidonic acid and eicosanoids, in mouse peritoneal macrophages.
