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J Med Chem. 2019 Feb 28;62(4):2172-2183. doi: 10.1021/acs.jmedchem.8b01908. Epub 2019 Feb 15.

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

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State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter , Chinese Academy of Sciences , 155 West Yangqiao Road , Fuzhou , Fujian 350002 , China.
University of Chinese Academy of Sciences , No.19 (A) Yuquan Road , Shijingshan District, Beijing 100049 , China.
College of Life Science , Fujian Agriculture and Forestry University , Fuzhou , Fujian 350002 , China.
College of Chemistry , Fuzhou University , Fuzhou , Fujian 350116 , China.
Department of Molecular Biology and Genetics , Aarhus University , Aarhus C 8000 , Denmark.


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.

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