Discovery and characterization of novel small-molecule CXCR4 receptor agonists and antagonists

The chemokine CXCL12 (SDF-1) and its cognate receptor CXCR4 are involved in a large number of physiological processes including HIV-1 infectivity, inflammation, tumorigenesis, stem cell migration, and autoimmune diseases. While previous efforts have identified a number of CXCR4 antagonists, there ha...

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Bibliographic Details
Published in:Scientific reports 2016-07, Vol.6 (1), p.30155-30155, Article 30155
Main Authors: Mishra, Rama K, Shum, Andrew K, Platanias, Leonidas C, Miller, Richard J, Schiltz, Gary E
Format: Article
Language:English
Subjects:
Anti-HIV Agents - chemistry
Anti-HIV Agents - pharmacology
Calcium - metabolism
Cell Line, Tumor
Chemotaxis, Leukocyte - drug effects
Crystallography, X-Ray
Databases, Factual
Drug Discovery
HEK293 Cells
High-Throughput Screening Assays
Humans
Molecular Structure
Receptors, CXCR4 - agonists
Receptors, CXCR4 - antagonists & inhibitors
Receptors, CXCR4 - drug effects
Receptors, CXCR4 - metabolism
Signal Transduction
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Summary:The chemokine CXCL12 (SDF-1) and its cognate receptor CXCR4 are involved in a large number of physiological processes including HIV-1 infectivity, inflammation, tumorigenesis, stem cell migration, and autoimmune diseases. While previous efforts have identified a number of CXCR4 antagonists, there have been no small molecule agonists reported. Herein, we describe the identification of a novel series of CXCR4 modulators, including the first small molecules to display agonist behavior against this receptor, using a combination of structure- and ligand-based virtual screening. These agonists produce robust calcium mobilization in human melanoma cell lines which can be blocked by the CXCR4-selective antagonist AMD3100. We also demonstrate the ability of these new agonists to induce receptor internalization, ERK activation, and chemotaxis, all hallmarks of CXCR4 activation. Our results describe a new series of biologically relevant small molecules that will enable further study of the CXCR4 receptor and may contribute to the development of new therapeutics.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep30155