Ispinesib (SB-715992)Kinesin spindle protein (KSP)inhibitor CAS# 336113-53-2 |
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Quality Control & MSDS
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Chemical structure
3D structure
| Cas No. | 336113-53-2 | SDF | Download SDF |
| PubChem ID | 6851740 | Appearance | Powder |
| Formula | C30H33ClN4O2 | M.Wt | 517.06 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | SB 715992 | ||
| Solubility | DMSO : ≥ 125 mg/mL (241.75 mM) H2O : < 0.1 mg/mL (insoluble) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | N-(3-aminopropyl)-N-[(1R)-1-(3-benzyl-7-chloro-4-oxoquinazolin-2-yl)-2-methylpropyl]-4-methylbenzamide | ||
| SMILES | CC1=CC=C(C=C1)C(=O)N(CCCN)C(C2=NC3=C(C=CC(=C3)Cl)C(=O)N2CC4=CC=CC=C4)C(C)C | ||
| Standard InChIKey | QJZRFPJCWMNVAV-HHHXNRCGSA-N | ||
| Standard InChI | InChI=1S/C30H33ClN4O2/c1-20(2)27(34(17-7-16-32)29(36)23-12-10-21(3)11-13-23)28-33-26-18-24(31)14-15-25(26)30(37)35(28)19-22-8-5-4-6-9-22/h4-6,8-15,18,20,27H,7,16-17,19,32H2,1-3H3/t27-/m1/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | High affinity allosteric kinesin spindle protein (KSP) inhibitor (Ki app = 1.7 nM). Exhibits >10,000-fold selectivity for KSP over a range of other mitotic kinesins. Inhibits proliferation and induces apoptosis of prostate and breast cancer cells in vitro. Induces tumor regression of breast cancer cell xenografts in mice. |
Ispinesib (SB-715992) Dilution Calculator
Ispinesib (SB-715992) Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.934 mL | 9.6701 mL | 19.3401 mL | 38.6802 mL | 48.3503 mL |
| 5 mM | 0.3868 mL | 1.934 mL | 3.868 mL | 7.736 mL | 9.6701 mL |
| 10 mM | 0.1934 mL | 0.967 mL | 1.934 mL | 3.868 mL | 4.835 mL |
| 50 mM | 0.0387 mL | 0.1934 mL | 0.3868 mL | 0.7736 mL | 0.967 mL |
| 100 mM | 0.0193 mL | 0.0967 mL | 0.1934 mL | 0.3868 mL | 0.4835 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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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].
References:
[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.
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Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer.[Pubmed:20068098]
Clin Cancer Res. 2010 Jan 15;16(2):566-76.
PURPOSE: Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein, a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have shown a 9% response rate in patients with locally advanced or metastatic breast cancer and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities, or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer, we explored the activity of ispinesib alone and in combination with several therapies approved for the treatment of breast cancer. EXPERIMENTAL DESIGN: We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo and tested the ability of ispinesib to enhance the antitumor activity of approved therapies. RESULTS: In vitro, ispinesib displayed broad antiproliferative activity against a panel of 53 breast cell lines. In vivo, ispinesib produced regressions in each of five breast cancer models and tumor-free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the antitumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine and exhibited activity comparable with paclitaxel and ixabepilone. CONCLUSIONS: These findings support further clinical exploration of kinesin spindle protein inhibitors for the treatment of breast cancer.
A phase II study of ispinesib (SB-715992) in patients with metastatic or recurrent malignant melanoma: a National Cancer Institute of Canada Clinical Trials Group trial.[Pubmed:17962907]
Invest New Drugs. 2008 Jun;26(3):249-55.
To assess the response rate and toxicity of the kinesin spindle protein (KSP) inhibitor, ispinesib, in malignant melanoma. Seventeen patients were enrolled from April to November 2005. Ispinesib was administered as a 1-hour infusion at a dose of 18 mg/m2 once every 3 weeks until disease progression. No objective responses were seen. Six patients (35%) had a best response of stable disease for a median duration of 2.8 months. Disease progression was documented in 9 (53%) after 1 or 2 cycles. Eighty-eight percent of patients received > or =90% of planned dose intensity. Grade 3 non-hematologic toxicities included dizziness (1) and blurred vision (1). There was one episode of febrile neutropenia, but no grade 3 or 4 biochemical adverse events. Pharmacokinetics was consistent with prior studies. KSP immunoreactivity was seen in 14 of 16 available archival tissue samples (88%). Ispinesib can be safely administered using the dose and schedule employed, with mild hematologic and non-hematologic toxicity. No objective responses were observed, and further development of single-agent ispinesib in malignant melanoma is not recommended. Although KSP expression appears to be common in melanoma, KSP may not be a suitable target for its treatment.
Mechanism of inhibition of human KSP by ispinesib.[Pubmed:18290633]
Biochemistry. 2008 Mar 18;47(11):3576-85.
KSP, also known as HsEg5, is a kinesin that plays an essential role in the formation of a bipolar mitotic spindle and is required for cell cycle progression through mitosis. Ispinesib is the first potent, highly specific small-molecule inhibitor of KSP tested for the treatment of human disease. This novel anticancer agent causes mitotic arrest and growth inhibition in several human tumor cell lines and is currently being tested in multiple phase II clinical trials. In this study we have used steady-state and pre-steady-state kinetic assays to define the mechanism of KSP inhibition by ispinesib. Our data show that ispinesib alters the ability of KSP to bind to microtubules and inhibits its movement by preventing the release of ADP without preventing the release of the KSP-ADP complex from the microtubule. This type of inhibition is consistent with the physiological effect of ispinesib on cells, which is to prevent KSP-driven mitotic spindle pole separation. A comparison of ispinesib to monastrol, another small-molecule inhibitor of KSP, reveals that both inhibitors share a common mode of inhibition.
Increased therapeutic potential of an experimental anti-mitotic inhibitor SB715992 by genistein in PC-3 human prostate cancer cell line.[Pubmed:16433906]
BMC Cancer. 2006 Jan 24;6:22.
BACKGROUND: Kinesin spindle proteins (KSP) are motor proteins that play an essential role in mitotic spindle formation. HsEg5, a KSP, is responsible for the formation of the bipolar spindle, which is critical for proper cell division during mitosis. The function of HsEg5 provides a novel target for the manipulation of the cell cycle and the induction of apoptosis. SB715992, an experimental KSP inhibitor, has been shown to perturb bipolar spindle formation, thus making it an excellent candidate for anti-cancer agent. Our major objective was a) to investigate the cell growth inhibitory effects of SB715992 on PC-3 human prostate cancer cell line, b) to investigate whether the growth inhibitory effects of SB715992 could be enhanced when combined with genistein, a naturally occurring isoflavone and, c) to determine gene expression profile to establish molecular mechanism of action of SB715992. METHODS: PC-3 cells were treated with varying concentration of SB715992, 30 microM of genistein, and SB715992 plus 30 microM of genistein. After treatments, PC-3 cells were assayed for cell proliferation, induction of apoptosis, and alteration in gene and protein expression using cell inhibition assay, apoptosis assay, microarray analysis, real-time RT-PCR, and Western Blot analysis. RESULTS: SB715992 inhibited cell proliferation and induced apoptosis in PC-3 cells. SB715992 was found to regulate the expression of genes related to the control of cell proliferation, cell cycle, cell signaling pathways, and apoptosis. In addition, our results showed that combination treatment with SB715992 and genistein caused significantly greater cell growth inhibition and induction of apoptosis compared to the effects of either agent alone. CONCLUSION: Our results clearly show that SB715992 is a potent anti-tumor agent whose therapeutic effects could be enhanced by genistein. Hence, we believe that SB715992 could be a novel agent for the treatment of prostate cancer with greater success when combined with a non-toxic natural agent like genistein.
