Virtual screening targeting the urokinase receptor, biochemical and cell-based studies, synthesis, pharmacokinetic characterization, and effect on breast tumor metastasis

Fang Wang, Jing Li, Anthony L. Sinn, W. Eric Knabe, May Khanna, Inha Jo, Jayne M. Silver, Kyungsoo Oh, Liwei Li, George E. Sandusky, George W. Sledge, Harikrishna Nakshatri, David R. Jones, Karen E. Pollok, Samy O. Meroueh

Research output: Contribution to journalArticle

18 Scopus citations


Virtual screening targeting the urokinase receptor (uPAR) led to (±)-3-(benzo[d][1,3]dioxol-5-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl) -4-phenylbutan-1-amine 1 (IPR-1) and N-(3,5-dimethylphenyl)-1-(4- isopropylphenyl)-5-(piperidin-4-yl)-1H-pyrazole-4-carboxamide 3 (IPR-69). Synthesis of an analogue of 1, namely, 2 (IPR-9), and 3 led to breast MDA-MB-231 invasion, migration and adhesion assays with IC 50 near 30 μM. Both compounds blocked angiogenesis with IC 50 of 3 μM. Compounds 2 and 3 inhibited cell growth with IC 50 of 6 and 18 μM and induced apoptosis. Biochemical assays revealed leadlike properties for 3, but not 2. Compound 3 administered orally reached peak concentration of nearly 40 μM with a half-life of about 2 h. In NOD-SCID mice inoculated with breast TMD-231 cells in their mammary fat pads, compound 3 showed a 20% reduction in tumor volumes and less extensive metastasis was observed for the treated mice. The suitable pharmacokinetic properties of 3 and the encouraging preliminary results in metastasis make it an ideal starting point for next generation compounds.

Original languageEnglish (US)
Pages (from-to)7193-7205
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number20
StatePublished - Oct 27 2011


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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