ArticleACS chemical biology2011
Targeting multiple conformations leads to small molecule inhibitors of the uPAR·uPA protein-protein interaction that block cancer cell invasion.
Article in ACS chemical biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 56 citations in OpenAlex.
- Review
- Identification of novel cholesterol metabolism-related biomarkers for thyroid cancer to predict the prognosis, immune infiltration, and drug sensitivity.Discover oncology · 2025Article
- GPLD1 Attenuates Heart Failure via Dual-Membrane Localization to Inhibit uPAR.Circulation research · 2025Article
- Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity.Clinical and translational allergy · 2023Article
- Urokinase-type plasminogen activator receptor (uPAR) as a therapeutic target in cancer.Journal of translational medicine · 2022Review
- Review
- 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
- Chemical Space Overlap with Critical Protein-Protein Interface Residues in Commercial and Specialized Small-Molecule Libraries.ChemMedChem · 2019Article
- Small-molecule CaProceedings of the National Academy of Sciences of the United States of America · 2018Article
- Toward Small-Molecule Inhibition of Protein-Protein Interactions: General Aspects and Recent Progress in Targeting Costimulatory and Coinhibitory (Immune Checkpoint) Interactions.Current topics in medicinal chemistry · 2018Review
- Mimicking Intermolecular Interactions of Tight Protein-Protein Complexes for Small-Molecule Antagonists.ChemMedChem · 2017Article
- A Computational Investigation of Small-Molecule Engagement of Hot Spots at Protein-Protein Interaction Interfaces.Journal of chemical information and modeling · 2017Article
- A novel peptide blocking cancer cell invasion by structure-based drug design.Biomedical reports · 2017Article
- Small Molecules Engage Hot Spots through Cooperative Binding To Inhibit a Tight Protein-Protein Interaction.Biochemistry · 2017Article
- HSP90 Inhibition Suppresses PGE2 Production via Modulating COX-2 and 15-PGDH Expression in HT-29 Colorectal Cancer Cells.Inflammation · 2016Article
- Structure-Based Virtual Ligand Screening on the XRCC4/DNA Ligase IV Interface.Scientific reports · 2016Article
- Re-engineering the Immune Response to Metastatic Cancer: Antibody-Recruiting Small Molecules Targeting the Urokinase Receptor.Angewandte Chemie (International ed. in English) · 2016Article
- Per-residue energy decomposition pharmacophore model to enhance virtual screening in drug discovery: a study for identification of reverse transcriptase inhibitors as potential anti-HIV agents.Drug design, development and therapy · 2016Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.