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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BORIS DOI
Date of Publication
December 6, 2018
Publication Type
Article
Division/Institute
Author
Evensen, Lasse | |
Lorens, James B. |
Series
ChemMedChem
ISSN or ISBN (if monograph)
1860-7179
Publisher
Wiley-VCH
Language
English
Publisher DOI
Description
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.
File(s)
File | File Type | Format | Size | License | Publisher/Copright statement | Content | |
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cmdc.201800554.pdf | text | Adobe PDF | 1.31 MB | publisher | published |