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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.

Author information

1
Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012, Bern, Switzerland.
2
Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3000, Bern 9, Switzerland.
3
Department of Biomedicine, Centre for Cancer Biomarkers (CCBIO), University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway.

Abstract

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 (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.

KEYWORDS:

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

PMID:
30520265
DOI:
10.1002/cmdc.201800554

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