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

Poirier, Marion; Awale, Mahendra; Rölli, Matthias A.; Giuffredi, Guy T.; Ruddigkeit, Lars; Evensen, Lasse; Stooss, Amandine; Calarco, Serafina; Lorens, James B.; Charles, Roch-Philippe; Reymond, Jean-Louis (2018). Identifying Lysophosphatidic Acid Acyltransferase β (LPAAT-β) as the Target of a Nanomolar Angiogenesis Inhibitor from a Phenotypic Screen Using the Polypharmacology Browser PPB2. ChemMedChem, 14(2), pp. 224-236. Wiley-VCH 10.1002/cmdc.201800554

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Poirier, Marion; Awale, Mahendra; Rölli, Matthias Andreas; Giuffredi, Guy Thierry; Ruddigkeit, Lars; Stooss, Amandine; Calarco, Serafina; Charles, Roch-Philippe and Reymond, Jean-Louis

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
500 Science > 540 Chemistry

ISSN:

1860-7179

Publisher:

Wiley-VCH

Language:

English

Submitter:

Sandra Tanja Zbinden Di Biase

Date Deposited:

19 Dec 2018 12:19

Last Modified:

26 Jan 2019 01:32

Publisher DOI:

10.1002/cmdc.201800554

BORIS DOI:

10.7892/boris.122708

URI:

https://boris.unibe.ch/id/eprint/122708

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