Abstract
The urokinase receptor (uPAR) serves as a docking site to the serine protease urokinase-type plasminogen activator (uPA) to promote extracellular matrix (ECM) degradation and tumor invasion and metastasis. Previously, we had reported a small molecule inhibitor of the uPAR·uPA interaction that emerged from structure-based virtual screening. Here, we measure the affinity of a large number of derivatives from commercial sources. Synthesis of additional compounds was carried out to probe the role of various groups on the parent compound. Extensive structure-based computational studies suggested a binding mode for these compounds that led to a structure-activity relationship study. Cellular studies in non-small cell lung cancer (NSCLC) cell lines that include A549, H460 and H1299 showed that compounds blocked invasion, migration and adhesion. The effects on invasion of active compounds were consistent with their inhibition of uPA and MMP proteolytic activity. These compounds showed weak cytotoxicity consistent with the confined role of uPAR to metastasis.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Benzoates / chemical synthesis
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Benzoates / chemistry
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Benzoates / pharmacology*
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Drug Design*
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Drug Screening Assays, Antitumor
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Humans
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Mannose-Binding Lectins / antagonists & inhibitors*
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Mannose-Binding Lectins / isolation & purification
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Mannose-Binding Lectins / metabolism
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Membrane Glycoproteins / antagonists & inhibitors*
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Membrane Glycoproteins / isolation & purification
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Membrane Glycoproteins / metabolism
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Molecular Dynamics Simulation*
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Molecular Structure
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Molecular Weight
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Piperidines / chemical synthesis
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Piperidines / chemistry
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Piperidines / pharmacology*
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Receptors, Cell Surface / antagonists & inhibitors*
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Receptors, Cell Surface / isolation & purification
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Receptors, Cell Surface / metabolism
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Structure-Activity Relationship
Substances
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2-((3-(3,5-dimethylpiperidin-1-yl)-6-oxo-6H-anthra(1,9-cd)isoxazol-5-yl)amino)benzoic acid
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Antineoplastic Agents
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Benzoates
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MRC2 protein, human
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Mannose-Binding Lectins
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Membrane Glycoproteins
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Piperidines
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Receptors, Cell Surface