4.7 Article

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

Journal

SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/srep30155

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Funding

  1. Chicago Biomedical Consortium
  2. Searle Funds at The Chicago Community Trust
  3. Cancer Center Support Grant from the National Cancer Institute [P30 CA060553]
  4. National Cancer Institute of the National Institutes of Health [R01CA189074]

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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.

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