Poirier, MarionMarionPoirierAwale, MahendraMahendraAwaleRölli, Matthias AndreasMatthias AndreasRölliGiuffredi, Guy ThierryGuy ThierryGiuffrediRuddigkeit, LarsLarsRuddigkeitEvensen, LasseLasseEvensenStooss, AmandineAmandineStoossCalarco, SerafinaSerafinaCalarcoLorens, James B.James B.LorensCharles, Roch-PhilippeRoch-PhilippeCharles0000-0002-5243-3866Reymond, Jean-LouisJean-LouisReymond0000-0003-2724-29422024-10-072024-10-072018-12-06https://boris-portal.unibe.ch/handle/20.500.12422/61670By screening a focused library of kinase inhibitor analogues in a phenotypic co‐culture assay for angiogenesis inhibition, we identified an aminotriazine that acts as a cytostatic nanomolar inhibitor. However, this aminotriazine was found to be completely inactive in a whole‐kinome profiling assay. To decipher its mechanism of action, we used the online target prediction tool PPB2 (http://ppb2.gdb.tools), which suggested lysophosphatidic acid acyltransferase β (LPAAT‐β) as a possible target for this aminotriazine as well as several analogues identified by structure–activity relationship profiling. LPAAT‐β inhibition (IC50 ≈15 nm) was confirmed in a biochemical assay and by its effects on cell proliferation in comparison with a known LPAAT‐β inhibitor. These experiments illustrate the value of target‐prediction tools to guide target identification for phenotypic screening hits and significantly expand the rather limited pharmacology of LPAAT‐β inhibitors.en500 - Science::570 - Life sciences; biology600 - Technology::610 - Medicine & health500 - Science::540 - Chemistryarticle10.7892/boris.12270810.1002/cmdc.201800554