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.
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Authors | Fang Wang, W Eric Knabe, Liwei Li, Inha Jo, Timmy Mani, Hartmut Roehm, Kyungsoo Oh, Jing Li, May Khanna, Samy O Meroueh |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 20
Issue 15
Pg. 4760-73
(Aug 01 2012)
ISSN: 1464-3391 [Electronic] England |
PMID | 22771232
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2012 Elsevier Ltd. All rights reserved. |
Chemical References |
- 2-((3-(3,5-dimethylpiperidin-1-yl)-6-oxo-6H-anthra(1,9-cd)isoxazol-5-yl)amino)benzoic acid
- Antineoplastic Agents
- Benzoates
- MRC2 protein, human
- Mannose-Binding Lectins
- Membrane Glycoproteins
- Piperidines
- Receptors, Cell Surface
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Topics |
- Antineoplastic Agents
(chemical synthesis, chemistry, pharmacology)
- Benzoates
(chemical synthesis, chemistry, pharmacology)
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Drug Design
- Drug Screening Assays, Antitumor
- Humans
- Mannose-Binding Lectins
(antagonists & inhibitors, isolation & purification, metabolism)
- Membrane Glycoproteins
(antagonists & inhibitors, isolation & purification, metabolism)
- Molecular Dynamics Simulation
- Molecular Structure
- Molecular Weight
- Piperidines
(chemical synthesis, chemistry, pharmacology)
- Receptors, Cell Surface
(antagonists & inhibitors, isolation & purification, metabolism)
- Structure-Activity Relationship
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