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ChemMedChem. 2019 Jan 22;14(2):224-236. doi: 10.1002/cmdc.201800554. Epub 2018 Dec 6.

Identifying Lysophosphatidic Acid Acyltransferase β (LPAAT-β) as the Target of a Nanomolar Angiogenesis Inhibitor from a Phenotypic Screen Using the Polypharmacology Browser PPB2.

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Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012, Bern, Switzerland.
Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3000, Bern 9, Switzerland.
Department of Biomedicine, Centre for Cancer Biomarkers (CCBIO), University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway.


By 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 (, 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.


angiogenesis; kinase inhibitors; phenotypic screening; polypharmacology; target prediction


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