Design, synthesis, biochemical studies, cellular characterization, and structure-based computational studies of small molecules targeting the urokinase receptor

Fang Wang, W. Eric Knabe, Liwei Li, Inha Jo, Timmy Mani, Hartmut Roehm, Kyungsoo Oh, Jing Li, May Khanna, Samy O. Meroueh

Research output: Contribution to journalArticle

24 Scopus citations


The urokinase receptor (uPAR) serves as a docking site to the serine protease urokinase-type plasminogen activator (uPA) to promote extracellular matrix (ECM) degradation and tumor invasion and metastasis. Previously, we had reported a small molecule inhibitor of the uPAR·uPA interaction that emerged from structure-based virtual screening. Here, we measure the affinity of a large number of derivatives from commercial sources. Synthesis of additional compounds was carried out to probe the role of various groups on the parent compound. Extensive structure-based computational studies suggested a binding mode for these compounds that led to a structure-activity relationship study. Cellular studies in non-small cell lung cancer (NSCLC) cell lines that include A549, H460 and H1299 showed that compounds blocked invasion, migration and adhesion. The effects on invasion of active compounds were consistent with their inhibition of uPA and MMP proteolytic activity. These compounds showed weak cytotoxicity consistent with the confined role of uPAR to metastasis.

Original languageEnglish (US)
Pages (from-to)4760-4773
Number of pages14
JournalBioorganic and Medicinal Chemistry
Issue number15
StatePublished - Aug 1 2012



  • Lung cancer
  • Metastasis
  • Protein-protein interaction
  • Small molecule inhibitors
  • Structure-activity relationship
  • Structure-based drug design
  • Synthesis
  • Urokinase receptor
  • Virtual screening

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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