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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Dong Wang, University of Chinese Academy of Sciences, State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences
  • ,
  • Yongshuai Yang, University of Chinese Academy of Sciences, Fujian Agriculture and Forestry University, State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences
  • ,
  • Longguang Jiang, Fuzhou University
  • ,
  • Yu Wang, Fujian Agriculture and Forestry University
  • ,
  • Jinyu Li, Fuzhou University
  • ,
  • Peter A. Andreasen
  • ,
  • Zhuo Chen, State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences
  • ,
  • Mingdong Huang, Fuzhou University, State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences
  • ,
  • Peng Xu, State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences

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.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume62
Issue4
Pages (from-to)2172-2183
Number of pages12
ISSN0022-2623
DOIs
Publication statusPublished - Feb 2019

See relations at Aarhus University Citationformats

ID: 160687237