Suppression of Tumor Growth and Metastases by Targeted Intervention in Urokinase Activity with Cyclic Peptides

Urokinase-type plasminogen activator
(uPA) is a diagnostic marker for breast and prostate cancers recommended
by American Society for Clinical Oncology and German Breast Cancer
Society. Inhibition of uPA was proposed as an efficient strategy for
cancer treatments. In this study, we report peptide-based uPA inhibitors
with high potency and specificity comparable to monoclonal antibodies.
We revealed the binding and inhibitory mechanisms by combining crystallography,
molecular dynamic simulation, and other biophysical and biochemical
approaches. Besides, we showed that our peptides efficiently inhibited
the invasion of cancer cells via intervening with the processes of
the degradation of extracellular matrices. Furthermore, our peptides
significantly suppressed the tumor growth and the cancer metastases
in tumor-bearing mice. This study demonstrates that these uPA peptides
are highly potent anticancer agents and reveals the mechanistic insights
of these uPA inhibitors, which can be useful for developing other
serine protease inhibitors.