ArticleBioorganic & medicinal chemistry2013
Small-molecule inhibition of the uPAR·uPA interaction: synthesis, biochemical, cellular, in vivo pharmacokinetics and efficacy studies in breast cancer metastasis.
Article in Bioorganic & medicinal chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Review
- Interface-driven structural evolution on diltiazem as novel uPAR inhibitors: from in silico design to in vitro evaluation.Molecular diversity · 2025Article
- Urokinase-type plasminogen activator (uPA) regulates invasion and matrix remodelling in colorectal cancer.Matrix biology plus · 2023Article
- Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer.Science advances · 2022Article
- Urokinase-type plasminogen activator receptor (uPAR) as a therapeutic target in cancer.Journal of translational medicine · 2022Review
- p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi.Science advances · 2021Article
- The Urokinase Receptor: A Multifunctional Receptor in Cancer Cell Biology. Therapeutic Implications.International journal of molecular sciences · 2021Review
- Design and Synthesis of Fragment Derivatives with a Unique Inhibition Mechanism of the uPAR·uPA Interaction.ACS medicinal chemistry letters · 2021Article
- Unconventional Secondary Structure Mimics: Ladder-Rungs.Angewandte Chemie (International ed. in English) · 2020Article
- Proteolysis is the most fundamental property of malignancy and its inhibition may be used therapeutically (Review).International journal of molecular medicine · 2019Review
- A novel peptide blocking cancer cell invasion by structure-based drug design.Biomedical reports · 2017Article
- Urokinase-type plasminogen activator receptor (uPAR) expression enhances invasion and metastasis in RAS mutated tumors.Scientific reports · 2017Article
- Small Molecules Engage Hot Spots through Cooperative Binding To Inhibit a Tight Protein-Protein Interaction.Biochemistry · 2017Article
- Urokinase type plasminogen activator receptor (uPAR) as a new therapeutic target in cancer.Translational medicine @ UniSa · 2016Article
- Re-engineering the Immune Response to Metastatic Cancer: Antibody-Recruiting Small Molecules Targeting the Urokinase Receptor.Angewandte Chemie (International ed. in English) · 2016Article
- Surfing the Protein-Protein Interaction Surface Using Docking Methods: Application to the Design of PPI Inhibitors.Molecules (Basel, Switzerland) · 2015Review
- A new class of orthosteric uPAR·uPA small-molecule antagonists are allosteric inhibitors of the uPAR·vitronectin interaction.ACS chemical biology · 2015Article
- Inhibition of urokinase-type plasminogen activator expression by dihydroartemisinin in breast cancer cells.Oncology letters · 2014Article
- Nonanebis(peroxoic acid): a stable peracid for oxidative bromination of aminoanthracene-9,10-dione.Beilstein journal of organic chemistry · 2014Article
- Probing binding and cellular activity of pyrrolidinone and piperidinone small molecules targeting the urokinase receptor.ChemMedChem · 2013Article
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Authors and funding
12 authors.
Funding
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 5h and peak concentration of 5 μM. Similar levels of the inhibitor were detected in tumor tissue up to 10h. 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.
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