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

Rama K. Mishra, Andrew K. Shum, Leonidas C. Platanias, Richard J. Miller, Gary E. Schiltz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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.

Original languageEnglish (US)
Article number30155
JournalScientific reports
StatePublished - Jul 26 2016

ASJC Scopus subject areas

  • General


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