GSK923295

Catalog No.S7090

GSK923295 Chemical Structure

Molecular Weight(MW): 592.13

GSK923295 is a first-in-class, specific allosteric inhibitor of CENP-E kinesin motor ATPase with Ki of 3.2 nM, and less potent to mutant I182 and T183. Phase 1.

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Cited by 7 Publications

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  • (f) HeLa cells were treated with mitotic kinesin CENP-E inhibitor GSK923295 (50 nM) for 1 h to generate misaligned kinetochores. After fixation, cells were stained for ACA, tubulin, and TIP60. Statistical significance was tested by two-sided t-test and represented by asterisks corresponding to ***, p < 0.001. Scale bars, 5 μm.

    Nat Chem Biol, 2016, 12(4):226-32.. GSK923295 purchased from Selleck.

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Description GSK923295 is a first-in-class, specific allosteric inhibitor of CENP-E kinesin motor ATPase with Ki of 3.2 nM, and less potent to mutant I182 and T183. Phase 1.
Features First potent, CENP-E-selective inhibitor that has been tested in Phase I clinical trials for treatment of Refractory Cancers.
Targets
CENP-E [1]
(Cell-free assay)
3.2 nM(Ki)
In vitro

GSK923295 is the first potent and selective inhibitor of the mitotic kinesin centromere-associated protein-E (CENP-E). [1][2] GSK923295 is uncompetitive with both ATP and microtubules (MT), inhibiting CENP-E MT-stimulated ATPase activity with a Ki of 3.2 nM, highly selective over other kinesins. GSK923295 inhibits release of inorganic phosphate and stabilizes CENP-E motor domain interaction with microtubules, reduces the rate of ATP-promoted dissociation of CENP-E from MT (koff, MT) by more than 50-fold. GSK923295 causes failure of metaphase chromosome alignment and induces mitotic arrest. GSK923295 is a potent inhibitor of tumor cell growth, with an average GI50 of 253 nM and a median GI50 of 32 nM for 237 tumor cell lines. [1] GSK923295 inhibits tumor cell growth more effectively when mitogen-activated protein kinase (MEK/ERK) signaling is also inhibited. [4]

In vivo GSK923295 produces clear increases in the abundance of mitotic figures and scattered apoptotic bodies in tumors. GSK923295 causes a dose-dependent increase in the ratio of 4n to 2n nuclei. GSK923295 exhibits robust, dose-dependent antitumor activity against Colo205 xenografts, including partial and complete regressions at the 125 mg/kg dose.[1] GSK923295 demonstrates significant antitumor activity against solid tumor models, inducing CRs in Ewing sarcoma, rhabdoid, and rhabdomyosarcoma xenografts, may be a valuable therapeutic target in pediatric cancer. [3]

Protocol

Kinase Assay:[1]
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Enzymology:

Kinesin motor domains are expressed in Escherichia coli BL21(DE3) and purified. CENP-E proteins includes residues 2–340 with a carboxyl-terminal 6-his tag. All studies using MT are conducted in PEM25 buffer [25mM PipesK+ (pH 6.8), 2mM MgCl2, 1mM EGTA] supplemented with 10 μM paclitaxel. The IC50 for steady-state inhibition is determined at 500 μM ATP, 5 μM MT, and 1 nM CENP-E in PEM25 buffer.
Cell Research:[1]
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  • Cell lines: Tumor cell lines
  • Concentrations: ~10 μM
  • Incubation Time: 72 h
  • Method: Cell-growth inhibition assays are performed by MDS in 384-well plates, and DNA content of fixed cells stained with DAPI using an Incell 1000 is analyzed. DNA content is determined 24 h after seeding (T0) and after exposure to varying concentrations of drug for an additional 72 h (T72). All T72 measurements are normalized to T0. Curves are analyzed using the XLfit curve-fitting tool to determine the concentration of GSK923295 yielding 50% growth inhibition relative to T0 and Ymax values (GI50).
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: mice bearing xenografts of the Colo205 colon tumor-cell line
  • Formulation: 4% N,N-dimethylacetamide (DMA)/Cremaphore (50/50) at pH 5.6
  • Dosages: 125 mg/kg, two cycles of three daily injections separated by 1 week
  • Administration: i.p.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 100 mg/mL (168.88 mM)
Ethanol 100 mg/mL (168.88 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 592.13
Formula

C32H38ClN5O4

CAS No. 1088965-37-0
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00504790 Completed Cancer GlaxoSmithKline June 25 2007 Phase 1
NCT00504790 Completed Cancer GlaxoSmithKline June 25 2007 Phase 1

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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.

Handling Instructions

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Kinesin Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID