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Author Notes:

E-mail: hshim@emory.edu (HS); dliotta@emory.edu (DCL); jsnyder@emory.edu (JPS)

For author contributions and acknowledgments, see the full article.

MSX-122 was developed by HS, DL, JS, WZ, and ZL, and its patent and IND are owned by Emory University. MSX-122 is not associated with any commercial entity. Otherwise the authors have declared that no competing interest exist. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.


Research Funding:

All the studies were funded by the United States National Institutes of Health.


  • Science & Technology
  • Multidisciplinary Sciences
  • HIV-1
  • AXIS
  • Mouse models
  • Metastasis
  • Inflammation
  • Cell binding assay
  • Cancer treatment
  • Animal models
  • Animal models of disease
  • Small molecules

Development of a Unique Small Molecule Modulator of CXCR4

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Journal Title:



Volume 7, Number 4


, Pages e34038-e34038

Type of Work:

Article | Final Publisher PDF


Background: Metastasis, the spread and growth of tumor cells to distant organ sites, represents the most devastating attribute and plays a major role in the morbidity and mortality of cancer. Inflammation is crucial for malignant tumor transformation and survival. Thus, blocking inflammation is expected to serve as an effective cancer treatment. Among anti-inflammation therapies, chemokine modulation is now beginning to emerge from the pipeline. CXC chemokine receptor-4 (CXCR4) and its ligand stromal cell-derived factor-1 (CXCL12) interaction and the resulting cell signaling cascade have emerged as highly relevant targets since they play pleiotropic roles in metastatic progression. The unique function of CXCR4 is to promote the homing of tumor cells to their microenvironment at the distant organ sites. Methodology/Principal Findings: We describe the actions of N,N'-(1,4-phenylenebis(methylene))dipyrimidin-2-amine (designated MSX-122), a novel small molecule and partial CXCR4 antagonist with properties quite unlike that of any other reported CXCR4 antagonists, which was prepared in a single chemical step using a reductive amination reaction. Its specificity toward CXCR4 was tested in a binding affinity assay and a ligand competition assay using 18F-labeled MSX-122. The potency of the compound was determined in two functional assays, Matrigel invasion assay and cAMP modulation. The therapeutic potential of MSX-122 was evaluated in three different murine models for inflammation including an experimental colitis, carrageenan induced paw edema, and bleomycin induced lung fibrosis and three different animal models for metastasis including breast cancer micrometastasis in lung, head and neck cancer metastasis in lung, and uveal melanoma micrometastasis in liver in which CXCR4 was reported to play crucial roles. Conclusions/Significance: We developed a novel small molecule, MSX-122, that is a partial CXCR4 antagonist without mobilizing stem cells, which can be safer for long-term blockade of metastasis than other reported CXCR4 antagonists.

Copyright information:

© 2012 Liang et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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