An inhibitor of cFMS kinase
GW2580 is a selective and?orally bioavailable inhibitor of Colony-stimulating-factor-1 receptor (CSF-1R) with IC50 value of 30nM [1]
GW2580 has been demonstrated to be an extremely selective inhibitor for CSF-1R and has been hypothesized to bind to the DFG-out mode of CSF-1R, which might lock it into an inactive conformation?[2] GW2580 has shown to inhibit epithelial cell-associated CSF-1 signaling, reduce Gr-1+?CD11b+?myeloid-derived suppressor cells (MDSCs) expansion, and alleviate the immune-suppressive microenvironment [3]. In addition, GW2580 suppressed IL-10 secretion in human glioblastoma cell line T98G [4].
参考文献:
[1] Conway JG1,?McDonald B,?Parham J,?Keith B,?Rusnak DW,?Shaw E,?Jansen M,?Lin P,?Payne A,?Crosby RM,?Johnson JH,?Frick L,?Lin MH,?Depee S,?Tadepalli S,Votta B,?James I,?Fuller K,?Chambers TJ,?Kull FC,?Chamberlain SD,?Hutchins JT. Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580. Proc Natl Acad Sci U S A.?2005 Nov 1;102(44):16078-83.
[2] Garcia AJ1,?Ruscetti M,?Arenzana TL,?Tran LM,?Bianci-Frias D,?Sybert E,?Priceman SJ,?Wu L,?Nelson PS,?Smale ST,?Wu H. Pten Null Prostate Epithelium Promotes Localized Myeloid-Derived Suppressor Cell Expansion and Immune Suppression during Tumor Initiation and Progression. Mol Cell Biol.?2014 Jun;34(11):2017-28.
[3] Kitagawa D1,?Gouda M,?Kirii Y,?Sugiyama N,?Ishihama Y,?Fujii I,?Narumi Y,?Akita K,?Yokota K. Characterization of kinase inhibitors using different phosphorylation states of colony stimulating factor-1 receptor tyrosine kinase. J Biochem.?2012 Jan;151(1):47-55.
[4] Komohara Y1,?Horlad H,?Ohnishi K,?Fujiwara Y,?Bai B,?Nakagawa T,?Suzu S,?Nakamura H,?Kuratsu J,?Takeya M. Importance of direct macrophage-tumor cell interaction on progression of human glioma. Cancer Sci.?2012 Dec;103(12):2165-72.
| Cell experiment [1]: | |
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Cell lines |
Mouse M-NFS-60 myeloid cell line and human monocytes |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
0- 20 μM |
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Applications |
GW2580 at 1 μM completely inhibited CSF-1-induced growth of mouse M-NFS-60 myeloid cells and human monocytes and completely inhibited bone degradation in cultures of human osteoclasts, rat calvaria, and rat fetal long bone. In contrast, GW2580 did not affect the growth of mouse NS0 lymphoblastoid cells, human endothelial cells, human fibroblasts, or five human tumor cell lines. |
| Animal experiment [1]: | |
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Animal models |
Xenograft mouse model with M-NFS-60 tumor cells |
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Dosage form |
Orally at 20 and 80 mg/kg twice a day |
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Application |
GW2580 was dosed orally at 20 and 80 mg/kg (b.i.d.), starting 1 h before the i.p. injection of M-NFS-60 cells, and the tumor cells in the peritoneal cavity were counted 4 days later. GW2580 produced a dose-related decrease in the number of tumor cells, with the 80 mg/kg dose completely blocking tumor growth. GW2580 showed no effect on body weights taken when the animals were killed. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1] Conway JG1, McDonald B, Parham J, Keith B, Rusnak DW, Shaw E, Jansen M, Lin P, Payne A, Crosby RM, Johnson JH, Frick L, Lin MH, Depee S, Tadepalli S,Votta B, James I, Fuller K, Chambers TJ, Kull FC, Chamberlain SD, Hutchins JT. Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16078-83. | |
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