Structural basis for therapeutic intervention of uPA/uPAR system

Curr Drug Targets. 2011 Nov;12(12):1729-43. doi: 10.2174/138945011797635911.


Urokinase-type plasminogen activator (uPA) is one of the two physiological serine proteases responsible for the activation of plasminongen to plasmin. uPA activity is regulated by its inhibitors (PAI-1 and PAI-2) and its receptor (uPAR), and an expanding list of their interacting proteins. In addition to plasminogen activation, this system also plays important roles in the regulation of many cellular processes including cell proliferation, adhesion and migration. It is beyond reasonable doubt that this enzyme system plays a central role in tumor biology and represents a high potential target for therapeutic intervention of tumor growth and metastasis. During the past fifteen years, crystal structures of uPA and its inhibitors have facilitated the development of uPA inhibitors. Many crystal structures of proteins in the uPA/uPAR system have also been reported recently, especially a series of structures of uPAR and its complexes with vitronectin and uPA, facilitating the development and evaluation of uPAR inhibitors. Recent progress on uPA inhibitors will be summarized in this article. The unique structural features and the druggable potentials of these new structures will also be discussed.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Biological Availability
  • Humans
  • Molecular Targeted Therapy*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacokinetics
  • Peptides, Cyclic / pharmacology
  • Peptides, Cyclic / therapeutic use
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Receptors, Urokinase Plasminogen Activator / antagonists & inhibitors*
  • Receptors, Urokinase Plasminogen Activator / chemistry*
  • Receptors, Urokinase Plasminogen Activator / metabolism
  • Signal Transduction / drug effects
  • Somatomedins / chemistry
  • Somatomedins / metabolism
  • Somatomedins / pharmacology
  • Somatomedins / therapeutic use
  • Translational Research, Biomedical
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors*
  • Urokinase-Type Plasminogen Activator / chemistry*
  • Urokinase-Type Plasminogen Activator / metabolism


  • Antineoplastic Agents
  • Peptides, Cyclic
  • Receptors, Urokinase Plasminogen Activator
  • Somatomedins
  • upain-1 peptide
  • Urokinase-Type Plasminogen Activator