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

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
10.7892/boris.122708
Date of Publication
December 6, 2018
Publication Type
Article
Division/Institute

Departement für Chemi...

Institut für Biochemi...

Author
Poirier, Marion
Departement für Chemie und Biochemie (DCB)
Awale, Mahendra
Departement für Chemie und Biochemie (DCB)
Rölli, Matthias Andreas
Institut für Biochemie und Molekulare Medizin (IBMM)
Giuffredi, Guy Thierry
Departement für Chemie und Biochemie (DCB)
Ruddigkeit, Lars
Departement für Chemie und Biochemie (DCB)
Evensen, Lasse
Stooss, Amandine
Institut für Biochemie und Molekulare Medizin (IBMM)
Calarco, Serafina
Institut für Biochemie und Molekulare Medizin (IBMM)
Lorens, James B.
Charles, Roch-Philippeorcid-logo
Institut für Biochemie und Molekulare Medizin (IBMM)
Reymond, Jean-Louisorcid-logo
Departement für Chemie und Biochemie (DCB)
Subject(s)

500 - Science::570 - ...

600 - Technology::610...

500 - Science::540 - ...

Series
ChemMedChem
ISSN or ISBN (if monograph)
1860-7179
Publisher
Wiley-VCH
Language
English
Publisher DOI
10.1002/cmdc.201800554
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.
Handle
https://boris-portal.unibe.ch/handle/20.500.12422/61670
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File(s)
FileFile TypeFormatSizeLicensePublisher/Copright statementContent
cmdc.201800554.pdftextAdobe PDF1.31 MBpublisherpublished restricted
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