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. 2019 Jan 22;14(2):224-236. doi: 10.1002/cmdc.201800554. Epub 2018 Dec 6.


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 (, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / antagonists & inhibitors*
  • Acyltransferases / genetics
  • Acyltransferases / isolation & purification
  • Angiogenesis Inducing Agents / metabolism*
  • Biological Assay / methods
  • Cell Culture Techniques
  • Cell Line
  • Cell Proliferation / drug effects
  • Drug Evaluation, Preclinical / methods
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Phenotype
  • Protein Binding
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism
  • Software
  • Structure-Activity Relationship
  • Triazines / chemistry*
  • Triazines / metabolism


  • Angiogenesis Inducing Agents
  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Triazines
  • Acyltransferases
  • 2-acylglycerophosphate acyltransferase