Ispinesib (SB-715992)
Catalog No.S1452 Synonyms: CK0238273
Molecular Weight(MW): 517.06
Ispinesib (SB-715992) is a potent, specific and reversible inhibitor of kinesin spindle protein (KSP) with Ki app of 1.7 nM in a cell-free assay, no inhibition to CENP-E, RabK6, MCAK, MKLP1, KHC or Kif1A. Phase 2.
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Representative photographs of fluorescent staining of microtubules and nuclei in MDA-MB-231 cells 24 h post-treatment with 4 nM of ispinesib or vinblastine or their combination. Arrows and arrowheads denote mitotic cells with monoploar and bipolar spindles, respectively. Scale bars, 20 um.
Mol Oncol 2014 8(8), 1548-60. Ispinesib (SB-715992) purchased from Selleck.
Original blot images and quantification of NKCC1 protein levels in the plasma membrane and cytosolic fractions of spinal cord slices with vehicle (Ctrl, 0.1% DMSO) or ispinesib (ISP, 1 uM). * p < 0.05; ** p < 0.01, compared with the vehicle control group. Error bars represent the S.E.
J Biol Chem 2014 289(45), 31111-20. Ispinesib (SB-715992) purchased from Selleck.
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KB-V1 cells were treated with BEZ235, BI 2536, IKK 16, ispinesib, and bryostatin-1 and then calcein AM (1 uM). Doses of each compound were generated from 1:2 dilutions of the highest concentration of 20 uM. The object intensities were plotted. Data presented are mean ± SD (n
=3).PLoS One 2013 8(4), e60334. Ispinesib (SB-715992) purchased from Selleck.
Flow cytometry-based efflux assays were performed to examine KB-V1 cells incubated with either calcein AM (1 uM, red line) or calcein AM plus BEZ235, BI 2536, IKK 16, ispinesib, or bryostatin-1 (5 uM, blue line).
PLoS One 2013 8(4), e60334. Ispinesib (SB-715992) purchased from Selleck.
Purity & Quality Control
Choose Selective Kinesin Inhibitors
Biological Activity
| Description | Ispinesib (SB-715992) is a potent, specific and reversible inhibitor of kinesin spindle protein (KSP) with Ki app of 1.7 nM in a cell-free assay, no inhibition to CENP-E, RabK6, MCAK, MKLP1, KHC or Kif1A. Phase 2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Features | An allosteric, potent, specific, and reversible inhibitor of the mitotic kinesin spindle protein (KSP) (HsEg5). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| In vitro |
Ispinesib is a potent, allosteric, reversible, and specific inhibitor of KSP, which changes the binding property of KSP to microtubules and disturbs its movement by inhibiting ADP release without altering the release of the KSP-ADP complex from the microtubule. [1] Ispinesib shows potent cytotoxic activity in a panel of tumor cell lines, including Colo205, Colo201, HT-29, M5076, Madison-109, and MX-1, with IC50 of 1.2 nM to 9.5 nM. [2] In PC-3 prostate cancer cells, Ispinesib (15 nM and 30 nM) blocks cell proliferation and induces apoptosis by regulating the expression levels of genes that controls apoptosis, cell proliferation, cell cycle, and cell signaling, such as EGFR, p27, p15, and IL-11. [3] In a panel of 53 breast cell lines, Ispinesib (7.4 nM–600 nM) demonstrates broad inhibitory activity. In BT-474 and MDA-MB-468 cells, Ispinesib (150 nM) induces apoptosis, as revealed by a higher proportion of apoptotic cells, lower antiapoptotic Bcl-XL level, and higher proapoptotic Bax and Bid levels. [4] |
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| Cell Data |
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| In vivo | Ispinesib (4.5 mg/kg–15 mg/kg) exhibits inhibitory effects against Colo205, Colo201, HT-29, but not MX-1 cells, in mouse xenograft models. SB-715992 (6 mg/kg–10 mg/kg ) also inhibits murine solid tumors, including Madison 109 lung carcinoma, M5076 sarcoma, as well as L1210 and P388 leukemias. [2] In mice xenograft models of breast cancer cells MCF-7, HCC1954, MDA-MB-468, and KPL4, Ispinesib (8 mg/kg–10 mg/kg) inhibits tumor growth. [4] |
Protocol
| Kinase Assay:[1] |
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Steady-State Kinetic Analysis of Human KSP ATPase Activity and Inhibition by Ispinesib: Kinesin specificity analysis is carried out using a pyruvate kinase-lactate dehydrogenase detection system that couples the production of ADP to oxidation of NADH. Absorbance changes are monitored at 340 nm. Steady-state studies using nanomolar concentrations of KSP are performed using a sensitive fluorescence-based assay utilizing a pyruvate kinase, pyruvate oxidase, and horseradish peroxidase (HRP) coupled detection system that couples the generation of ADP to oxidation of Amplex Red to fluorescent resorufin. Generation of resorufin is monitored by fluorescence (λexcitation = 520 nm and λemission = 580 nm). Steady-state biochemical experiments are performed in PEM25 buffer [25 mM Pipes-K+ (pH 6.8), 2 mM MgCl2, 1 mM EGTA] supplemented with 10 µM paclitaxel for experiments involving microtubules. The IC50 for steady-state inhibition is determined at 500 µM ATP, 5 µM Microtubules, and 1 nM KSP in PEM25 buffer. Ki app (apparent inhibitor dissociation constant) values of Ispinesib are extracted from the dose-response curves, with explicit correction for enzyme concentration by using the Morrison equation. Inhibitor modality (e.g., competitive, noncompetitive, uncompetitive, or mixed) under steady-state conditions is determined by measuring the effect of inhibitor concentration on initial velocity as a function of substrate concentrations. Data are fit using equations in GraFit to velocity equations for the various modes of inhibition. |
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| Cell Research:[4] |
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| Animal Research:[4] |
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Solubility (25°C)
| In vitro | DMSO | 103 mg/mL (199.2 mM) |
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| Ethanol | 103 mg/mL (199.2 mM) | |
| Water | Insoluble |
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Information
| Molecular Weight | 517.06 |
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| Formula | C30H33ClN4O2 |
| CAS No. | 336113-53-2 |
| Storage | powder |
| in solvent | |
| Synonyms | CK0238273 |
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Clinical Trial Information
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT00607841 | Completed | Breast Neoplasms | Cytokinetics | December 2007 | Phase 1|Phase 2 |
| NCT00363272 | Completed | Childhood Burkitt Lymphoma|Childhood Central Nervous System Germ Cell Tumor|Childhood Choroid Plexus Tumor|Childhood Craniopharyngioma|Childhood Grade I Meningioma|Childhood Grade II Meningioma|Childhood Grade III Meningioma|Childhood High-grade Cerebral Astrocytoma|Childhood Infratentorial Ependymoma|Childhood Low-grade Cerebral Astrocytoma|Childhood Spinal Cord Neoplasm|Childhood Supratentorial Ependymoma|Recurrent Childhood Brain Stem Glioma|Recurrent Childhood Brain Tumor|Recurrent Childhood Cerebellar Astrocytoma|Recurrent Childhood Cerebral Astrocytoma|Recurrent Childhood Ependymoma|Recurrent Childhood Grade III Lymphomatoid Granulomatosis|Recurrent Childhood Large Cell Lymphoma|Recurrent Childhood Lymphoblastic Lymphoma|Recurrent Childhood Medulloblastoma|Recurrent Childhood Small Noncleaved Cell Lymphoma|Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor|Recurrent Childhood Visual Pathway and Hypothalamic Glioma|Unspecified Childhood Solid Tumor Protocol Specific | National Cancer Institute (NCI) | June 2006 | Phase 1 |
| NCT00354250 | Completed | Recurrent Renal Cell Cancer|Stage III Renal Cell Cancer|Stage IV Renal Cell Cancer | National Cancer Institute (NCI) | May 2006 | Phase 2 |
| NCT00096499 | Completed | Adenocarcinoma of the Prostate|Recurrent Prostate Cancer|Stage IV Prostate Cancer | National Cancer Institute (NCI) | April 2005 | Phase 2 |
| NCT00103311 | Completed | Recurrent Colon Cancer|Recurrent Rectal Cancer|Stage IIIA Colon Cancer|Stage IIIA Rectal Cancer|Stage IIIB Colon Cancer|Stage IIIB Rectal Cancer|Stage IIIC Colon Cancer|Stage IIIC Rectal Cancer|Stage IVA Colon Cancer|Stage IVA Rectal Cancer|Stage IVB Colon Cancer|Stage IVB Rectal Cancer | National Cancer Institute (NCI) | January 2005 | Phase 2 |
| NCT00095628 | Completed | Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma|Recurrent Metastatic Squamous Neck Cancer With Occult Primary|Recurrent Salivary Gland Cancer|Recurrent Squamous Cell Carcinoma of the Hypopharynx|Recurrent Squamous Cell Carcinoma of the Larynx|Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity|Recurrent Squamous Cell Carcinoma of the Oropharynx|Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity|Recurrent Verrucous Carcinoma of the Larynx|Recurrent Verrucous Carcinoma of the Oral Cavity|Stage IV Squamous Cell Carcinoma of the Hypopharynx|Stage IV Squamous Cell Carcinoma of the Larynx|Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity|Stage IV Squamous Cell Carcinoma of the Oropharynx|Stage IV Verrucous Carcinoma of the Larynx|Stage IV Verrucous Carcinoma of the Oral Cavity|Stage IVA Salivary Gland Cancer|Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity|Stage IVB Salivary Gland Cancer|Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity|Stage IVC Salivary Gland Cancer|Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity | National Cancer Institute (NCI) | January 2005 | Phase 2 |
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