pi103 and 5-(2-2-difluorobenzo(1-3)dioxol-5-ylmethylene)thiazolidine-2-4-dione

Endothelial cells play a central role in inflammatory responses, mediating leukocyte and solute traffic from blood vessels into the tissue, and are therefore key targets for anti-inflammatory therapies. Phosphoinositide 3-kinases (PI3Ks) are important signal transducers in inflammation and cancer, however there are 8 different PI3K catalytic isoforms, several of which have been shown to play distinct roles in cellular responses. Isoform-selective inhibitors have recently been described, but their effects on endothelial cell responses have not been compared. Here we compare the effects of the pan-PI3K inhibitor wortmannin with that of four more isoform-selective inhibitors, PI-103, TGX-221, AS604850 and IC87114, on endothelial cells stimulated with the pro-inflammatory cytokine TNFα. We find that PI-103 and wortmannin are most effective at reducing both endothelial permeability and leukocyte transendothelial migration (TEM), which correlates with a decrease in both the activity of the tyrosine kinase Pyk2 and its association with VE-cadherin. PI-103-related compounds are therefore likely to be good candidates for treating chronic inflammatory responses involving TNFα.

Topics: Adenine; Androstadienes; Antigens, CD; Cadherins; Capillary Permeability; Cell Membrane Permeability; Cell Shape; Class Ia Phosphatidylinositol 3-Kinase; Dioxoles; Endothelial Cells; Focal Adhesion Kinase 2; Furans; Human Umbilical Vein Endothelial Cells; Humans; Leukocytes; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Binding; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyridines; Pyrimidines; Quinazolines; Signal Transduction; Thiazolidinediones; TOR Serine-Threonine Kinases; Transendothelial and Transepithelial Migration; Tumor Necrosis Factor-alpha; Wortmannin