Targeting multiple conformations leads to small molecule inhibitors of the uPAR•uPA protein-protein interaction that block cancer cell invasion

May Khanna, Fang Wang, Inha Jo, W. Eric Knabe, Sarah M. Wilson, Liwei Li, Khuchtumur Bum-Erdene, Jing Li, George W. Sledge, Rajesh Khanna, Samy O. Meroueh

Research output: Contribution to journalArticle

37 Scopus citations


Interaction of the urokinase receptor (uPAR) with its binding partners such as the urokinase-type plasminogen activator (uPA) at the cell surface triggers a series of proteolytic and signaling events that promote invasion and metastasis. Here, we report the discovery of a small molecule (IPR-456) and its derivatives that inhibit the tight uPAR•uPA protein-protein interaction. IPR-456 was discovered by virtual screening against multiple conformations of uPAR sampled from explicit-solvent molecular dynamics simulations. Biochemical characterization reveal that the compound binds to uPAR with submicromolar affinity (K d = 310 nM) and inhibits the tight protein-protein interaction with an IC 50 of 10 μM. Free energy calculations based on explicit-solvent molecular dynamics simulations suggested the importance of a carboxylate moiety on IPR-456, which was confirmed by the activity of several derivatives including IPR-803. Immunofluorescence imaging showed that IPR-456 inhibited uPA binding to uPAR of breast MDA-MB-231 tumor cells with an IC 50 of 8 μM. The compounds blocked MDA-MB-231 cell invasion, but IPR-456 showed little effect on MDA-MB-231 migration and no effect on adhesion, suggesting that uPAR mediates these processes through its other binding partners.

Original languageEnglish (US)
Pages (from-to)1232-1243
Number of pages12
JournalACS Chemical Biology
Issue number11
StatePublished - Nov 18 2011
Externally publishedYes


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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