Identifying Lysophosphatidic Acid Acyltransferase β (LPAAT-β) as the Target of a Nanomolar Angiogenesis Inhibitor from a Phenotypic Screen Using the Polypharmacology Browser PPB2
| Autor: | Serafina Calarco, Guy T. Giuffredi, James B. Lorens, Roch-Philippe Charles, Lasse Evensen, Amandine Stooss, Lars Ruddigkeit, Jean-Louis Reymond, Mahendra Awale, Matthias A. Roelli, Marion Poirier |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular Angiogenesis Phenotypic screening Cell Culture Techniques Drug Evaluation Preclinical 01 natural sciences Biochemistry Cell Line Small Molecule Libraries Inhibitory Concentration 50 Structure-Activity Relationship Drug Discovery Human Umbilical Vein Endothelial Cells medicine Humans Enzyme Inhibitors General Pharmacology Toxicology and Pharmaceutics IC50 Cell Proliferation Pharmacology Molecular Structure Triazines 010405 organic chemistry Chemistry Kinase Cell growth Organic Chemistry Assay 0104 chemical sciences 3. Good health Angiogenesis inhibitor 010404 medicinal & biomolecular chemistry Phenotype Mechanism of action Molecular Medicine Angiogenesis Inducing Agents Biological Assay medicine.symptom Acyltransferases Software Protein Binding |
| Zdroj: | ChemMedChem. 14:224-236 |
| ISSN: | 1860-7179 |
| DOI: | 10.1002/cmdc.201800554 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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