Small-molecule inhibition of the uPAR·uPA interaction: Synthesis, biochemical, cellular, in vivo pharmacokinetics and efficacy studies in breast cancer metastasis

Timmy Mani, Fang Wang, William Eric Knabe, Anthony L. Sinn, May Khanna, Inha Jo, George E. Sandusky, George W. Sledge, David R. Jones, Rajesh Khanna, Karen E. Pollok, Samy O. Meroueh

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

The uPAR·uPA protein-protein interaction (PPI) is involved in signaling and proteolytic events that promote tumor invasion and metastasis. A previous study had identified 4 (IPR-803) from computational screening of a commercial chemical library and shown that the compound inhibited uPAR·uPA PPI in competition biochemical assays and invasion cellular studies. Here, we synthesize 4 to evaluate in vivo pharmacokinetic (PK) and efficacy studies in a murine breast cancer metastasis model. First, we show, using fluorescence polarization and saturation transfer difference (STD) NMR, that 4 binds directly to uPAR with sub-micromolar affinity of 0.2 μM. We show that 4 blocks invasion of breast MDA-MB-231, and inhibits matrix metalloproteinase (MMP) breakdown of the extracellular matrix (ECM). Derivatives of 4 also inhibited MMP activity and blocked invasion in a concentration- dependent manner. Compound 4 also impaired MDA-MB-231 cell adhesion and migration. Extensive in vivo PK studies in NOD-SCID mice revealed a half-life of nearly 5 h and peak concentration of 5 μM. Similar levels of the inhibitor were detected in tumor tissue up to 10 h. Female NSG mice inoculated with highly malignant TMD-MDA-MB-231 in their mammary fat pads showed that 4 impaired metastasis to the lungs with only four of the treated mice showing severe or marked metastasis compared to ten for the untreated mice. Compound 4 is a promising template for the development of compounds with enhanced PK parameters and greater efficacy.

Original languageEnglish (US)
Pages (from-to)2145-2155
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number7
DOIs
StatePublished - Apr 1 2013

Keywords

  • Breast cancer
  • Cancer
  • In vivo
  • Metastasis
  • Protein-protein interaction inhibitors
  • 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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