Exploiting polypharmacology to dissect host kinases and kinase inhibitors that modulate endothelial barrier integrity

Cell Chem Biol. 2021 Dec 16;28(12):1679-1692.e4. doi: 10.1016/j.chembiol.2021.06.004. Epub 2021 Jul 2.

Abstract

Kinase inhibitors are promising drugs to stabilize the endothelial barrier following inflammatory damage. However, our limited knowledge of how kinase signaling activates barrier-restorative pathways and the complexity of multi-target drugs have hindered drug discovery and repurposing efforts. Here, we apply a kinase regression approach that exploits drug polypharmacology to investigate endothelial barrier regulation. A screen of 28 kinase inhibitors identified multiple inhibitors that promote endothelial barrier integrity and revealed divergent barrier phenotypes for BCR-ABL drugs. Target deconvolution predicted 50 barrier-regulating kinases from diverse kinase families. Using gene knockdowns, we identified kinases with a role in endothelial barrier regulation and dissected different mechanisms of action of barrier-protective kinase inhibitors. These results demonstrate the importance of polypharmacology in the endothelial barrier phenotype of kinase inhibitors and provide promising new leads for barrier-strengthening therapies.

Keywords: BCR-ABL; endothelial barrier permeability; host kinases; kinase inhibitors; kinase regression; polypharmacology; thrombin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology*
  • Carbazoles / chemistry
  • Carbazoles / pharmacology*
  • Cell Line
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Humans
  • Indole Alkaloids / chemistry
  • Indole Alkaloids / pharmacology*
  • Nitriles / chemistry
  • Nitriles / pharmacology*
  • Phosphotransferases / antagonists & inhibitors*
  • Phosphotransferases / genetics
  • Phosphotransferases / metabolism
  • Polypharmacology
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Signal Transduction / drug effects

Substances

  • Aniline Compounds
  • Carbazoles
  • Indole Alkaloids
  • Nitriles
  • Protein Kinase Inhibitors
  • Quinolines
  • bosutinib
  • staurosporine aglycone
  • Phosphotransferases