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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 known as GSK-923295A) is a novel, potent, first-in-class, specific and allosteric inhibitor of CENP-E (centromere-associated protein E) kinesin motor ATPase with Ki of 3.2 nM, and it is less potent to mutant I182 and T183. GSK-923295 is an antimitotic inhibitor of centromere-associated protein E (CENP-E) with potential anticancer activity. GSK923295A demonstrated significant antitumor activity against solid tumor models, inducing CRs in Ewing sarcoma, rhabdoid, 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 923295; GSK-923295; GSK-923295A; GSK923295A; 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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