Abstract
BackgroundMetastasis, 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 FindingsWe 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/SignificanceWe 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.
Highlights
Chemokines are small, pro-inflammatory cytokines of approximately 10 kDa that orchestrate a diverse set of activities through interaction with their cognate receptors
CXCL12 can interact with the CXCR7 chemokine receptor [25,26], our screening was specific for CXC chemokine receptor-4 (CXCR4), since the MDAMB-231 cells used for primary screening express insignificant levels of CXCR7 (Figure 1C)
Effective concentration for MSX122 was at a low nanomolar
Summary
Chemokines are small, pro-inflammatory cytokines of approximately 10 kDa that orchestrate a diverse set of activities through interaction with their cognate receptors. Coupling of stromal cell derived factor 1 (SDF-1; CXCL12) with its receptor CXCR4, which was previously identified as a major coreceptor for the entry of T-tropic HIV [1,2,3,4], plays critical roles in inflammation [5], as well as cancer metastasis [6]. The CXCR4/ CXCL12-axis has been shown to play a pivotal role in trafficking and homing of normal stem cells and metastasis of cancer stem cells to organs that express high levels of CXCL12, such as the lymph nodes, lungs, liver, and bone [10,11]. 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
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