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    DBeQ (JRF 12)
    DBeQ (JRF 12)

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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 #: V1319
    CAS #: 177355-84-9Purity ≥98%

    Description: DBeQ (JRF-12; JRF 12; JRF12) is a reversible and ATP-competitive p97 inhibitor with potential antineoplastic activity. It inhibits p97 with an IC50 of 1.5 μM. DBeQ can be used for treatment of cancer by impairing both ubiquitin-dependent and autophagic protein clearance pathways. 

    References: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4834-9; Proc Natl Acad Sci U S A. 2012 Nov 27;109(48):19733-8. 

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    Molecular Weight (MW)340.42
    FormulaC22H20N4
    CAS No.177355-84-9
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 68 mg/mL (199.8 mM)
    Water: <1 mg/mL
    Ethanol: 5 mg/mL (14.7 mM)
    SMILES Code C12=CC=CC=C1N=C(NCC3=CC=CC=C3)N=C2NCC4=CC=CC=C4
    SynonymsJRF-12; DBeQ; JRF 12; JRF12; DBEQ;  


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    In Vitro

    In vitro activity: DBeQ blocks UbG76V-GFP, ODD-Luc and Luc-ODC degradation with IC50 of 2.6 μM, 56 μM and 45 μM in HeLa cells. DBeQ is at least 50-fold less potent toward N-ethylmaleimide–sensitive factor (NSF) and 26S proteasome. DBeQ inhibits p97 competitively with respect to ATP, with Ki of 3.2 μM, suggesting that it binds to the active site of the D2 domain. DBeQ (10 μM) potently blocks degradation of TCRα-GFP in HEK293 cells. DBeQ induces CHOP within 3 hours in a concentration-dependent manner but does not increase p21 level in HEK293 cells. DBeQ (15 μM) induces a strong accumulation of LC3-II in the nucleus plus membrane-enriched and cytosolic fractions in Hela cells. DBeQ acts by blocking autophagic degradation of LC3-II instead of inducing autophagy in HeLa cells. DBeQ (10 μM) rapidly promotes activation of the “executioner” caspases-3 and -7 in HeLa cells. DBeQ activates the intrinsic caspase-9 apoptotic pathway more than the extrinsic caspase-8 pathway, whereas STS activates both pathways to a similar extent. DBeQ is fivefold more active against multiple myeloma (RPMI8226) cells than normal human fetal lung fibroblasts (MRC5), with HeLa and Hek293 cells showing intermediate sensitivities. DBeQ exhibits 20-fold selectivity for stabilizing p97-dependent vs. independent UPS reporter substrates in HeLa cells. DBeQ impairs degradation of substrates within the ERAD and autophagy pathways. DBeQ (12 μM) inhibits intracellular neutralization in a dose-dependent manner in HeLa cells. DBeQ (10 μM), which completely inhibits degradation of virus and antibody in the fate-of-capsid experiment, fails to prevent degradation of IgG Fc. DBeQ (9 μM) reduces the initial gradient of neutralization as a function of antibody concentration. DBeQ decreases both basal and nutrient-stimulated phosphorylation of MTOR targets similar to the effects of rapamycin in U20S cells.


    Kinase Assay: Assay Buffer [20 μL of 2.5× concentration, where 1× = 50 mM Tris (pH 7.4), 20 mM MgCl2, 1 mM EDTA, and 0.5 mM tris(2-carboxyethyl)phosphine (TCEP)] is dispensed into each well of a 96-well plate. Purified p97 (25 μL of 50 μM) is diluted in 975 μL of 1× Assay Buffer, and 10 μL is dispensed in each well. DBeQ (10 μL) or 5% DMSO (10 μL) is then added to each well, and the plate is incubated at room temperature for 10 min. The ATPase assay is carried out by adding to each well 10 μL of 500 μM ATP (pH 7.5), incubating at room temperature for 60 min, and then adding 50 μL Kinase Glo Plus reagent, followed by a final 10-min incubation at room temperature in the dark. Luminescence is read on an Analyst AD. DBeQ is assayed at a range of concentrations (0, 0.048, 0.24, 1.2, 6, and 30 μM) in triplicate. 


    Cell Assay: Cells (MRC-5, Hek293, HeLa and RPMI8226 cells) are seeded on a 384-well solid white plate (5,000 cells/well). Cells are transfected with luciferase siRNA or p97 siRNA (10 nM) for 48 hours or treated with DBeQ for the indicated amount of time. Caspase-3/7 Glo, caspase-6 Glo, caspase-8 Glo, or caspase-9 Glo is added into each well and mixed by shaking at 500 rpm for 1 min. Luminescence signal is determined after incubation at room temperature for 1 hour. Cellular viability is determined with CellTiter-Glo reagen. To determine the IC50 of cellular viability, cells are treated with MG132 or DBeQ at seven concentrations (threefold serial dilutions starting at 33 μM) for 48 hours. IC50 values are calculated from fitting the percentage of luminescence signal normalized to DMSO treated cells).

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    References

    Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4834-9; Proc Natl Acad Sci U S A. 2012 Nov 27;109(48):19733-8.


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

    DBeQ

    DBeQ impairs the ERAD pathway.  2011 Mar 22;108(12):4834-9. 

    DBeQ

    DBeQ impairs the autophagy pathway.  2011 Mar 22;108(12):4834-9. 
     

    DBeQ

    DBeQ (1) is a reversible and selective inhibitor of p97.   2011 Mar 22;108(12):4834-9. 

    DBeQ

    VCP is essential for TRIM21-mediated neutralization of AdV by antibody.  2012 Nov 27;109(48):19733-8.

    DBeQ

    VCP is required for degradation of virus and antibody in ADIN but not for TRIM21-mediated degradation of cytosolic IgG Fc.  2012 Nov 27;109(48):19733-8.

     

    DBeQ

    VCP is essential for efficient and potent ADIN.  2012 Nov 27;109(48):19733-8.


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