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    GSK923295 (GSK-923295A)
    GSK923295 (GSK-923295A)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V1629
    CAS #: 1088965-37-0 Purity ≥98%

    Description: GSK923295 (also called GSK-923295; GSK923295A; GSK 923295; GSK-923295A) is a first-in-class, specific and allosteric antimitotic inhibitor of CENP-E (centromere-associated protein E, kinesin motor ATPase) with potential antitumor activity. It inhibits CENP-E with a Ki of 3.2 nM, and it is less potent against mutant I182 and T183. GSK923295A has demonstrated high antitumor activity against various solid tumor models such as CRs in rhabdoid, Ewing sarcoma, and rhabdomyosarcoma xenografts. 

    References: Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5839-44; Pediatr Blood Cancer. 2012 Jun;58(6):916-23. 

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    Molecular Weight (MW)592.13
    FormulaC32H38ClN5O4 
    CAS No.1088965-37-0
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 100 mg/mL (168.9 mM)
    Water:<1 mg/mL
    Ethanol: 100 mg/mL (168.9 mM)
    SMILES O=C(N[[email protected]@H](CC1=CC=C(C2=CN3C=CC=C([[email protected]@H](O)C)C3=N2)C=C1)CNC(CN(C)C)=O)C4=CC=C(OC(C)C)C(Cl)=C4 
    Synonyms GSK923295; GSK-923295A; GSK 923295; GSK923295A; GSK-923295; GSK 923295A.


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    In Vitro

    In vitro activity: GSK923295 is the first potent and selective inhibitor of the mitotic kinesin centromere-associated protein-E (CENP-E). 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. GSK923295 inhibits tumor cell growth more effectively when mitogen-activated protein kinase (MEK/ERK) signaling is also inhibited.


    Kinase Assay: 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 Assay: 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).

    In VivoGSK923295 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. 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.
    Animal modelMice bearing xenografts of the Colo205 colon tumor-cell line 
    Formulation & DosageDissolved in 4% N,N-dimethylacetamide (DMA)/Cremaphore (50/50) at pH 5.6; 125 mg/kg; i.p. injection 
    References

    Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5839-44; Pediatr Blood Cancer. 2012 Jun;58(6):916-23. 


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    GSK923295

    GSK923295 inhibits microtubule (MT)-stimulated ATPase of CENP-E and promotes formation of a MT-bound complex. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5839-44.
     

    GSK923295

    Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5839-44. Antitumor activity of GSK923295.


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