Abstract
The C-X-C chemokine receptor type 4 (CXCR4)/stromal cell derived factor-1 (SDF-1 or CXCL12) interaction and the resulting cell signaling cascade play a key role in metastasis and inflammation. On the basis of the previously published CXCR4 antagonist 5 (WZ811), a series of novel nonpeptidic anti-CXCR4 small molecules have been designed and synthesized to improve potency. Following a structure-activity profile around 5, more advanced compounds in the N,N'-(1, 4-phenylenebis(methylene)) dipyrimidin-2-amines series were discovered and shown to possess higher CXCR4 binding potential and specificity than 5. Compound 26 (508MCl) is the lead compound and exhibits subnanomolar potency in three in vitro assays including competitive binding, Matrigel invasion and Gα(i) cyclic adenosine monophosphate (cAMP) modulation signaling. Furthermore, compound 26 displays promising effects by interfering with CXCR4 function in three mouse models: paw inflammation, Matrigel plug angiogenesis, and uveal melanoma micrometastasis. These data demonstrate that dipyrimidine amines are unique CXCR4 antagonists with high potency and specificity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amines / chemical synthesis*
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Amines / chemistry
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Amines / pharmacology
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Angiogenesis Inhibitors / chemical synthesis*
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Angiogenesis Inhibitors / chemistry
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Angiogenesis Inhibitors / pharmacology
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Binding, Competitive
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Collagen
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Drug Combinations
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Female
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Inflammation / drug therapy
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Laminin
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Melanoma / drug therapy
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Melanoma / pathology
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Mice
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Mice, Nude
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Neoplasm Metastasis
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Neovascularization, Pathologic / drug therapy
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Proteoglycans
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Pulmonary Fibrosis / drug therapy
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Receptors, CXCR4 / antagonists & inhibitors*
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Structure-Activity Relationship
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Uveal Neoplasms / drug therapy
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Uveal Neoplasms / pathology
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Xenograft Model Antitumor Assays
Substances
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Amines
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Angiogenesis Inhibitors
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Anti-Inflammatory Agents, Non-Steroidal
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CXCR4 protein, mouse
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Drug Combinations
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Laminin
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Proteoglycans
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Pyrimidines
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Receptors, CXCR4
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matrigel
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Collagen