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    XL888
    XL888

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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 #: V0887
    CAS #: 1149705-71-4Purity ≥98%

    Description: XL888 (XL-888; XL 888) is an orally bioavailable, ATP-competitive inhibitor of HSP90 (Heat Shock Protein 90) with potential antitumor activity. It inhibits HSP90 with an IC50 of 24 nM. It exhibits excellent in vivo antitumor efficacy in mice bearing M229R xenografts

    References: Bioorg Med Chem Lett. 2012 Sep 1;22(17):5396-404; Clin Cancer Res. 2012 May 1;18(9):2502-14. 

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    Molecular Weight (MW)503.64
    FormulaC29H37N5O3
    CAS No.1149705-71-4
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 100 mg/mL (198.6 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)30% PEG400+0.5% Tween80+5% propylene glycol: 30mg/mL  
    Synonyms

    XL-888; XL 888; XL888; 

    Chemical Name: 5-((R)-sec-butylamino)-N1-((1R,3s,5S)-8-(5-(cyclopropanecarbonyl)pyridin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2-methylterephthalamide

    InChi Key: LHGWWAFKVCIILM-CIQXWFTPSA-N

    InChi Code: InChI=1S/C29H37N5O3/c1-4-17(3)32-25-14-23(16(2)11-24(25)28(30)36)29(37)33-20-12-21-8-9-22(13-20)34(21)26-10-7-19(15-31-26)27(35)18-5-6-18/h7,10-11,14-15,17-18,20-22,32H,4-6,8-9,12-13H2,1-3H3,(H2,30,36)(H,33,37)/t17-,20-,21-,22+/m1/s1

    SMILES Code: O=C(NC1=CC=C(CCN2CC3=C(C=C(OC)C(OC)=C3)CC2)C=C1)C4=CC=CC(/C=C(C(N(C)/C5=C\C6=CC=CC=C6)=O)\NC5=O)=C


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    In Vitro

    In vitro activity: XL888 induces HER2 degradation in NCI-N87 cells with IC50 of 56 nM. XL888 inhibits the proliferation of HER2 over-expressed NCI-N87, HER2 over-expressed BT-474, HER2 over-expressed MDA-MB-453, MET mutated MKN45, B-Raf mutated Colo-205, B-Raf mutated SK-MEL-28, EGFR mutated HN5, EGFR mutated NCI-H1975, PI3K mutated MCF7, and K-Ras mutated A549 with IC50 of 21.8, 0.1, 16.0, 45.5, 11.6, 0.3, 5.5, 0.7, 4.1 and 4.3 nM. XL888 leads to dose-dependent decreases in the growth of vemurafenib-naive and vemurafenib-resistant melanoma cell lines and melanoma cell lines with intrinsic resistance with IC50 of all around 0.1 μM. The growth inhibitory effects of XL888 are associated with induction of either a G1-phase cell-cycle arrest (WM164, M229, M229R, M249, M249R, 1205Lu, and WM39 cell lines) or a G2-M phase cell-cycle arrest (WM164R, 1205LuR, and RPMI 7951 cell lines). XL888 (300 nmol) induces high levels ( > 66%) of apoptosis, and loss of mitochondrial membrane potential (TMRM) in these cell lines. The cytotoxic effects of XL888 are durable with no signs of colony formation observed in any of the cell lines even cultured up to 4 weeks. XL888 treatment (300 nM, 48 hours) leads to the degradation of IGF1R, PDGFRβ, ARAF, CRAF, and cyclin D1 and the inhibition of AKT, ERK, and S6 signaling in all of the cell lines with acquired BRAF inhibitor resistance. treatment of cell lines that are naive, intrinsically resistant, and with acquired vemurafenib resistance. Treatment with XL888 (300 nM) leads to robust time-dependent increases in the expression of HSP70 isoform 1. XL888 (48 hours, 300 nM) treatment increases the expression of BIM-EL, BIM-L, and BIM-S expression in the M229R, 1205LuR, RPMI7951, and WM39 cell lines, induces expression of BIM-L and BIM-S in the WM164R cell line, and BIM-EL in the M249R cell line.


    Cell Assay:  Cells are plated at a density of 2?05 per mL and left to grow overnight before being treated with increasing concentrations of XL888. After incubation with XL888 for 3 days, Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assays are performed.

    In VivoXL888 (100 mg/kg) significantly induces the regression of, or growth inhibition (50%) of established M229R and 1205LuR xenografts in SCID mice. 15 days of XL888 treatment showes a robust (8.6-fold) increase in intratumoral HSP70 expression compared with controls. XL888 treatment is noted to be proapoptotic in vivo and leads to increased TUNEL staining in M229R xenografts associated with increased expression of BIM and decreased expression of Mcl-1.
    Animal modelMice bearing M229R xenografts
    Formulation & DosageDissolved in 10 mM HCl; 100 mg/kg; oral gavage
    References

    Bioorg Med Chem Lett. 2012 Sep 1;22(17):5396-404; Clin Cancer Res. 2012 May 1;18(9):2502-14.


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

    XL888

    The HSP90 inhibitor XL888 blocks the growth and survival of melanoma cell lines with diverse mechanisms of vemurafenib resistance. Clin Cancer Res. 2012 May 1;18(9):2502-14.

    XL888

    XL888 degrades proteins involved in BRAF inhibitor resistance leading to apoptosis induction. Clin Cancer Res. 2012 May 1;18(9):2502-14.

     


    XL888

    HSP90 inhibition is more effective at restoring the apoptotic response than combined MEK+PI3K inhibition. Clin Cancer Res. 2012 May 1;18(9):2502-14.

    XL888

    Development of a quantitative pharmacodynamic assay for HSP90 inhibition. Clin Cancer Res. 2012 May 1;18(9):2502-14.

    XL888

    XL888 induces the regression of established M229R xenografts and is associated with increased intratumoral HSP70 expression. Clin Cancer Res. 2012 May 1;18(9):2502-14.

    XL888

    HSP90 inhibition increased BIM, decreases Mcl-1 and restores apoptosis in vemurafenib-resistant melanoma cell lines. Clin Cancer Res. 2012 May 1;18(9):2502-14.


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