wz-811 and Inflammation

CXCR4 and its cognate ligand CXCL12 has been linked to various pathways such as cancer metastasis, inflammation, HIV-1 proliferation, and auto-immune diseases. Small molecules have shown potential as CXCR4 inhibitors and modulators, and therefore can mitigate diseases related to the CXCR4-CXCL12 pathway. We have designed and synthesized a series of 2,5-diamino and 2,5-dianilinomethyl pyridine derivatives as potential CXCR4 antagonists. Thirteen compounds have an effective concentration (EC) of 100 nM or less in a binding affinity assay and nine of these have at least 75% inhibition of invasion in Matrigel binding assay. Compounds 3l, 7f, 7j, and 7p show a minimal reduction in inflammation when carrageenan paw edema test is conducted. Overall, these compounds show potential as CXCR4 antagonist.

Topics: Animals; Carrageenan; Dose-Response Relationship, Drug; Drug Design; Edema; Humans; Inflammation; Mice; Molecular Structure; Pyridines; Receptors, CXCR4; Structure-Activity Relationship

The interaction between G-Protein coupled receptor CXCR4 and its natural ligand CXCL12 has been linked to inflammation experienced by patients with Irritable Bowel Disease (IBD). Blocking this interaction could potentially reduce inflammatory symptoms in IBD patients. In this work, several thiophene-based and furan-based compounds modeled after AMD3100 and WZ811-two known antagonists that interrupt the CXCR4-CXCL12 interaction-were synthesized and analyzed. Fifteen hit compounds were identified; these compounds exhibited effective concentrations (EC) lower than 1000 nM (AMD3100) and inhibited invasion of metastatic cells by at least 45%. Selected compounds (2d, 2j, 8a) that inhibited metastatic invasion at a higher rate than WZ811 (62%) were submitted for a carrageenan inflammation test, where both 8a and 2j reduced inflammation in the same range as WZ811 (40%) but did not reduce inflammation more than 40%. Select compounds were also modeled in silico to show key residue interactions. These preliminary results with furan-based and thiophene-based analogues contribute to the new class on heterocyclic aromatic-based CXCR4 antagonists.

Topics: Animals; Carrageenan; Cell Line, Tumor; Dose-Response Relationship, Drug; Furans; Heterocyclic Compounds; Hindlimb; Humans; Inflammation; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Structure; Receptors, CXCR4; Structure-Activity Relationship; Thiophenes

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.

Topics: Amines; Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Binding, Competitive; Collagen; Drug Combinations; Female; Inflammation; Laminin; Melanoma; Mice; Mice, Nude; Neoplasm Metastasis; Neovascularization, Pathologic; Proteoglycans; Pulmonary Fibrosis; Pyrimidines; Receptors, CXCR4; Structure-Activity Relationship; Uveal Neoplasms; Xenograft Model Antitumor Assays