SB743921

Catalog No.S2182

SB743921 is a kinesin spindle protein (KSP) inhibitor with Ki of 0.1 nM, almost no affinity to MKLP1, Kin2, Kif1A, Kif15, KHC, Kif4 and CENP-E. Phase 1/2.

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SB743921 Chemical Structure

SB743921 Chemical Structure
Molecular Weight: 553.52

Validation & Quality Control

2 customer reviews :

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Product Description

Biological Activity

Description SB743921 is a kinesin spindle protein (KSP) inhibitor with Ki of 0.1 nM, almost no affinity to MKLP1, Kin2, Kif1A, Kif15, KHC, Kif4 and CENP-E. Phase 1/2.
Targets KSP (MX1 cells) [1] KSP (Colo205 cells) [1] KSP [1] KSP (SKOV3 cells) [1]

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IC50 0.06 nM 0.07 nM 0.1 nM(Ki) 0.2 nM
In vitro The Ki of SB 743921 for human and mouse KSP is 0.1 nM and 0.12 nM, respectively, while the Ki of SB 743921 for other kinesins including MKLP1, Kin2 is more than 70 μM. SB 743921 blocks assembly of a functional mitotic spindle, thereby causing cell cycle arrest in mitosis and subsequent cell death. SB-743921 has improved potency over ispinesib in both biochemical and cellular assays. [1]
In vivo SB-743921 is greater efficacy in vivo against P388 leukemia. SB-743921 has significant efficacy in a broad spectrum of tumor models differing from that of taxanes. SB-743921 is shown to have activity against advanced human tumor xenografts Colo205 (complete regressions), MCF-7, SK-MES, H69, OVCAR-3 (complete and partial regressions), and HT-29, MX-1, MDA-MB-231, A2780 (tumor growth delay). SB-743921 doesn't cause the neuropathy often associated with the tubulin agents. [1]
Features

Protocol(Only for Reference)

Kinase Assay: [2]

Biochemistry assay The motor domains of KSP (amino acids 1–360) is expressed as in Escherichia coli BL21(DE3) as COOH-terminal 6-his fusion proteins. Bacterial pellets are lysed in a microfluidizer with a lysis buffer [50 mM Tris-HCl; 50 mM KCl, 10 mM imidazole, 2 mM MgCl2, 8 mM β-mercaptoethanol, 0.1 mM ATP (pH 7.4)], and proteins are purified using Ni-NTA agarose affinity chromatography, with an elution buffer consisting of 50 mM PIPES, 10% sucrose, 300 mM imidazole, 50 mM KCl, 2 mM MgCl2, mM β-mercaptoethanol, and 0.1 mM ATP (pH 6.8). Steady-state measurements of ATPase activity are performed with a pyruvate kinase–lactate dehydrogenase detection system that coupled the appearance of ADP with oxidation of NADH. Absorbance changes are monitored at 340 nm. All biochemical experiments are performed in PEM25 buffer [25 mM Pipes/KOH (pH 6.8), 2 mM MgCl2, 1 mM EGTA] supplemented with 10 μM SB 743921 for experiments involving microtubules. Rates of ADP release are measured in a stopped-flow apparatus; the decrease in fluorescence of MANT-ATP is monitored. Rates of Pi release are measured in a stopped-flow apparatus, using bacterial phosphate binding protein modified with 7-diethylamino-3-((((2 maleimidyl)ethyl)amino)carbonyl)coumarin (MDCC) dye. Ki estimates of KSP inhibitors are extracted from the dose–response curves, with explicit correction for enzyme concentration. Tubulin polymerization by measuring changes in absorbance at 340 nm is monitored. The assay is performed in 100-μL volumes in 96-well half-area microtiter plates, using a microplate reader with the incubation temperature set at 37 °C.

Cell Assay: [2]

Cell lines HeLa cells
Concentrations ~1 μM
Incubation Time 24 hours
Method All cells including HeLa cells are cultured in 10% FCS in RPMI 1640 in 5% CO2. We assessed 48-hour growth inhibition by serial dilution of SB 743921 relative to DMSO-treated cells in 96-well microtiter plates, using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium. Cell growth is represented as the ratio of absorbance of treated cells to DMSO control, plotted by concentration and fitted to a four-parameter curve. Concentrations at which cellular growth is inhibited by 50% are extrapolated from the curve fit. The DNA content of HeLa cells cultured in the presence or absence of 1 μM SB 743921 for 24 hours is assessed by propidium iodide staining and flow cytometry. Immunofluorescence images are collected of HeLa cells treated for 24 hours with 1 μM SB 743921, fixed with 2% formaldehyde, permeabilized, and stained with DM1-α, anti-γ-tubulin, and 1 μg/mL 4′,6-diamidino-2-phenylindole, and with Alexa 488 secondary goat antirabbit IgG and Rhodamine-X goat antimouse IgG. Images are collected with a DeltaVision Restoration Microscopy System at a magnification of ×600. Z stacks (0.2 μm) are collected, and out of focus information is removed by constrained iterative deconvolution. Z stacks are then compressed into to a single image plane.

Animal Study: [1]

Animal Models Female BDF1 mice with P388 lymphocytic leukemia cells
Formulation 2% dimethylacetamide + 2% Cremophor EL + 96% acidified water [pH 5.0]
Dosages 7.5 mg/kg- 30 mg/kg
Administration Administered via i.p.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Jackson JR, et al. AACR, 2006, Abst 0906.

[2] Sakowicz R, et al. Cancer Res, 2004, 64(9), 3276-3280.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-23)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00343564 Completed Non-Hodgkins Lymphoma|Hodgkins Disease Cytokinetics April 2006 Phase 1|Phase 2
NCT00136513 Completed Solid Tumor Cancer GlaxoSmithKline April 2004 Phase 1

Chemical Information

Download SB743921 SDF
Molecular Weight (MW) 553.52
Formula

C31H33N2O3.HCl

CAS No. 940929-33-9
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 111 mg/mL (200.53 mM)
Ethanol 111 mg/mL (200.53 mM)
Water 22 mg/mL (39.74 mM)
In vivo Saline pH5.0 30 mg/mL
* <1 mg/ml means slightly soluble or 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 Name (R)-N-(3-aminopropyl)-N-(1-(3-benzyl-7-chloro-4-oxo-4H-chromen-2-yl)-2-methylpropyl)-4-methylbenzamide hydrochloride

Customer Product Validation(2)


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Rating
Source Mol Oncol 2014 8(8):1404-18. SB743921 purchased from Selleck
Method Infrared imaging
Cell Lines HeLa cells
Concentrations 0-50 nM
Incubation Time 1-5 days
Results Incubation of iRFP expressing HeLa cells with SB743921 induced growth inhibition in a dose-dependent manner.

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Rating
Source Leuk Lymphoma 2014 1-8. SB743921 purchased from Selleck
Method Western blot analysis
Cell Lines KCL22 cells
Concentrations 0.5, 1, 3 nM
Incubation Time 48 h
Results The underlying mechanism whereby SB743921 induces apoptosis after prolonged mitotic arrest is not completely understood. iT detected that KSP protein was decreased in KCL22 cells treated with SB743921. SB743921 treatment also decreased AKT and ERK phosphorylation of both K562 cells and KCL22 cells. These results clearly demonstrate that inhibition of AKT and ERK coincided with the mitotic cell death of SB743921 treated CML cells.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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