CXCR4 antagonist
WZ811 is a small molecule antagonist of CXC chemokine receptor 4 (CXCR4) [1].
WZ811 is synthesized with two aromatic amine moieties. It is found to effectively inhibit TN14003 binding to CXCR4 with EC50 value of 0.3nM at first. And then WZ811 is found to have ability in counteracting SDF-1 function and blocking CXCR4/SDF-1-mediated signaling. In the cAMP assay, WZ811 reduces the effect on cAMP caused by 150ng/ml SDF-1 significantly. It also blocks the SDF-1 induced Matrigel invasion with EC50 value of 5.2nM. Since CXCR4 is involved in the pathogeneses of a wide range of infectious, inflammatory and other diseases, WZ811 is developed for the treatment of various CXCR4-related diseases. It is reported to have weak anti-HIV activity in cell culture [1, 2].
参考文献:
[1] Zhan W, Liang Z, Zhu A, et al. Discovery of small molecule CXCR4 antagonists. Journal of medicinal chemistry, 2007, 50(23): 5655-5664.
[2] Choi W T, Duggineni S, Xu Y, et al. Drug discovery research targeting the CXC chemokine receptor 4 (CXCR4). Journal of medicinal chemistry, 2011, 55(3): 977-994.
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Cell experiment: |
In brief, cells are treated with WZ811 at 37°C for 24 h. After collection and washing with phosphate-buffered saline (PBS) buffer, cells are resuspended with staining buffer at a final density of 1 × 106/mL. Then, 5 μL annexin V-APC is added to 100 μL cell suspensions and incubated at room temperature in the dark for 10 min. Finally, cells are analyzed with FACS Calibur to determine cell apoptosis profiles[2]. |
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Animal experiment: |
Mice[2]A total of 1 × 106 TF-1 cells in 100 μL of PBS are injected subcutaneously into dorsal flanks of an immunodeficient nude mouse. The animals are treated with WZ811 (40 mg/kg), or WZ811 once daily by oral gavage once the tumors have reached 100 mm3. Tumor growth and body weight is measured every three days during the treatment. The tumor volume (TV) is calculated every 3 days according to the following standard formula: TV (mm3) = length × width2 × 0.5[2]. |
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参考文献: [1]. WZ811, et al. Discovery of small molecule CXCR4 antagonists. J Med Chem. 2007 Nov 15;50(23):5655-64. |
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