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    A-1155463
    A-1155463

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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 #: V2657
    CAS #: 1235034-55-5Purity ≥98%

    Description: A-1155463 is a novel highly potent and selective BCL-XL inhibitor that shows picomolar binding affinity to BCL-XL (Ki <0.01  nM), and >1000-fold weaker binding to BCL-2 (Ki = 80 nM) and related proteins BCL-W (Ki = 19 nM) and MCL-1 (Ki > 440 nM). It was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. A-1155463 represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization. A-1155463 demonstratsstrong growth inhibition of over half of the colorectal cell lines as defined by EC50 values ≤0.5 μM in the presence of 10 % FBS.  A-1155463 is substantially more potent against BCL-XL-dependent cell lines relative to WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses.  

    References: ACS Med Chem Lett. 2014 Aug 26;5(10):1088-93; Sci Transl Med. 2015 Mar 18;7(279):279ra40.


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    Molecular Weight (MW)669.79 
    FormulaC35H32FN5O4S2 
    CAS No.1235034-55-5 
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 100 mg/mL (149.3 mM) 
    Water: <1 mg/mL
    Ethanol: 100 mg/mL (149.3 mM) 
    Solubility (In vivo) O=C(C1=C(CCCOC2=CC=C(C#CCN(C)C)C=C2F)SC(N3CC4=C(C=CC=C4C (NC5=NC6=CC=CC=C6S5)=O)CC3)=N1)O
    Synonyms A-1155463; A 1155463; A1155463.


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    In Vitro

    In vitro activity: A-1155463 disrupts BCL-XL-BIM but not BCL-2-BIM complexes in cells. A-1155463 kills BCL-XL-dependent Molt-4 cells (EC50=70 nM) but has no measurable cytotoxicity against BCL-2-dependent RS4;11 cells (EC50>5 mM). A-1155463 induces the hallmarks of apoptosis, as evidenced by the release of cytochrome c from mitochondria, caspase activation, and the accumulation of caspase-dependent sub-G0-G1 DNA content in BCL-XL-dependent H146 cells.


    Kinase Assay: A-1155463 is a highly potent and selective BCL-XL inhibitor, A-1155463 shows picomolar binding affinity to BCL-XL (Ki <0.01  nM), and >1000-fold weaker binding to BCL-2 (Ki = 80 nM) and related proteins BCL-W (Ki = 19 nM) and MCL-1 (Ki > 440 nM).


    Cell Assay: Cells are treated with increasing concentration of A-1155463. Cells are assayed for viability after 72 h using the CellTiter-Glo luminescent cell viability assay according to the manufacturer’s protocol. Results are normalized to cells without treatment. EC50 is calculated using the GraphPad Prism software.

    In VivoA-1155463 causes a mechanism-based and reversible thrombocytopenia in mice and inhibits H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses.  he ability of A-1155463 to exert in vivo on-target activity was demonstrated through a rapid and reversible reduction in platelets in SCID-Beige mice following a single IP dose. Additionally, administration of A-1155463 to tumor bearing SCID-Beige mice afforded modest but statistically significant tumor growth inhibition. Detailed mechanistic studies of A-1155463 and combination activity with relevant chemotherapy across multiple tumor types will be reported in an accompanying manuscript. Following a single 5 mg/kg IP dose of A-1155463 in nontumor bearing SCID-Beige mice, platelet counts fall dramatically as measured at 6 h postdose and then rebound to normal levels within 72 h. Daily Dosing at 5 mg/kg IP to SCID-Beige mice that had been inoculated with BCL-XL-dependent H146 tumor cells for 14 days causes a statistically significant inhibition of tumor growth (maximum tumor growth inhibition = 44%), which is alleviated upon cessation of dosing. 
    Animal modelSCID-Beige Mice 
    Formulation & DosageFormulated in 5% DMSO, 10% EtOH, 20% Cremaphor ELP, and 65% D5W; 5 mg/kg; i.p. 
    References

    ACS Med Chem Lett. 2014 Aug 26;5(10):1088-93; Sci Transl Med. 2015 Mar 18;7(279):279ra40; Molecular Cancer. 2015, 14(1):1-9. 


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

    A-1155463

    (a) Kinetics of platelet reduction and rebound following a single IP dose of A-1155463 in SCID-Beige mice.  2014 Aug 26;5(10):1088-93.

     

    A-1155463

    X-ray crystal structure of A-1155463 (green) bound to BCL-XL.  2014 Aug 26;5(10):1088-93.

     A-1155463


    X-ray crystal structure of compound 10 (green) bound to BCL-XL.  2014 Aug 26;5(10):1088-93.


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