An Eg5 inhibitor
Ispinesib (SB-715992) is a selective inhibitor of KSP with IC50 value of 0.5 nM [1].
Kinesin spindle protein (KSP) is a kinesin motor protein and plays an important role in the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. It has been shown that abnormal expression of KSP is correlated with a variety of human cancers and its inhibitors may be a promising anticancer agent [2] [3].
Ispinesib (SB-715992) is a potent KSP inhibitor and often combines with chemotherapy drugs to tumor treatment. When tested with a panel of 23 tumor cell lines, Ispinesib (SB-715992) treatment showed high activity to inhibit KSP in most of the cell lines while only Rh18 having an IC50 value greater than 1 μM (median IC50=4.1 nM, maximum IC50=0.5 nM) by using PPTP method [1]. In a panel of 53 breast cell lines, Ispinesib (SB-715992) exhibits broad antiproliferative activity and up-regulated the expression of both mitotic and apoptotic markers in MDA-MB-468 cell line [2]. When tested with PC-3 cells, Ispinesib (SB-715992) treatment inhibits cell proliferation, inducs cell apoptosis and up-regulated the expressions of genes that related to the control of cell proliferation, cell cycle, cell signaling pathways and apoptosis [3].
In mouse model with 26 tumor cells subcutaneous xenograft, administration of Ispinesib (SB-715992) inducs markedly tumor growth delay with the percent of 88% (23/26) and maintained completed response (CR) in the rhaboid tumor, Wilms tumor and Ewing sarcoma xenograft mouse model [1].
参考文献:
[1].? Carol, H., et al., Initial testing (stage 1) of the kinesin spindle protein inhibitor ispinesib by the pediatric preclinical testing program. Pediatr Blood Cancer, 2009. 53(7): p. 1255-63.
[2].? Purcell, J.W., et al., Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer. Clin Cancer Res, 2010. 16(2): p. 566-76.
[3].? Davis, D.A., et al., Increased therapeutic potential of an experimental anti-mitotic inhibitor SB715992 by genistein in PC-3 human prostate cancer cell line. BMC Cancer, 2006. 6: p. 22.
| Cell experiment [1]: | |
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Cell lines |
BT-474, MD A-MB-468 cell lines |
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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 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
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Reaction Conditions |
72 h; GI50=45 nM (BT-474), GI50=19 nM (MD A-MB-468) |
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Applications |
Cells were treated with increasing concentrations of ispinesib and ranked according to the concentration of drug required to reduce growth by 50%. The GI50 values were 45 nM and 19 nM for BT-474 and MD A-MB-468 cell lines, respectively. |
| Animal experiment [1]: | |
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Animal models |
Nude nu/nu mice, SCID mice |
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Dosage form |
8 mg/kg (SCID), 10 mg/kg (nude); Intraperitoneal injection |
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Applications |
Mice bearing tumor xenografts of MDA-MB-468 was treated i.p. with ispinesib at its MTD (SCID, 8 mg/kg; nude, 10 mg/kg) on its optimal q4d×3 schedule. The triple-negative xenograft model MDA-MB-468, among the most sensitive lines in vitro, exhibited the greatest ispinesib sensitivity in vivo. On ispinesib treatment, MDA-MB-468 tumors regressed completely in all mice, each scoring as TFS at the end of the study and 30 days beyond. |
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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] Purcell J W, Davis J, Reddy M, et al. Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer[J]. Clinical Cancer Research, 2010, 16(2): 566-576. | |
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