Numerous studies have shown a paradoxical positive correlation between elevated levels of
plasminogen activator inhibitior-1 (PAI-1) in
tumors and blood of
cancer patients with poor clinical outcome, suggesting that
PAI-1 could be a therapeutic target. Here we tested two orally bioavailable small molecule inhibitors of
PAI-1 (
TM5275 and
TM5441) for their efficacy in pre-clinical models of
cancer. We demonstrated that these inhibitors decreased cell viability in several human
cancer cell lines with an IC50 in the 9.7 to 60.3 μM range and induced intrinsic apoptosis at concentrations of 50 μM. In vivo,
oral administration of
TM5441 (20 mg/kg daily) to HT1080 and HCT116 xenotransplanted mice increased
tumor cell apoptosis and had a significant disruptive effect on the
tumor vasculature that was associated with a decrease in
tumor growth and an increase in survival that, however, were not statistically significant. Pharmacokinetics studies indicated an average peak plasma concentration of 11.4 μM one hour after
oral administration and undetectable levels 23 hours after administration. The effect on
tumor vasculature in vivo was further examined in endothelial cells (EC) in vitro and this analysis indicated that both
TM5275 and
TM5441 inhibited EC branching in a 3D
Matrigel assay at concentrations where they had little effect on EC apoptosis. These studies bring novel insight on the activity of
PAI-1 inhibitors and provide important information for the future design of inhibitors targeting
PAI-1 as therapeutic agents in
cancer.