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    b-AP15 (NSC 687852)
    b-AP15 (NSC 687852)

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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 #: V1329
    CAS #: 1009817-63-3Purity ≥98%

    Description: b-AP15 (formerly known as NSC687852; b-AP15; USP14 Inhibitor III; b-AP-15; NSC-687852) is a novel, potent and specific deubiquitinase (DUB) inhibitor of 19S proteasomes activity of Ub-AMC cleavage with potential antineoplastic activity. It inhibits deubiquitinase with an IC50 of 2.1 μM. b-AP15 displays antitumor activity in several preclinical solid tumor models. b-AP15 also triggers time- and dose-dependent apoptosis of the human multiple myeloma (MM) cell lines RPMI8226 and U266, as determined by phosphatidylserine exposure. Furthermore, b-AP15 triggered processing of pro-caspase-3 and cleavage of poly (ADP-ribose) polymerase in MM cells. b-AP15 also induced caspase-independent apoptosis in primary human natural killer cells. Taken together, b-AP15 may have potential for treatment of multiple myeloma patients.

    References: Nat Med. 2011 Nov 6;17(12):1636-40; Int J Biochem Cell Biol. 2012 Nov;44(11):1729-38. 

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    Molecular Weight (MW)419.39
    FormulaC22H17N3O6
    CAS No.1009817-63-3
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 48 mg/mL (114.5 mM)
    Water:<1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)4% DMSO+corn oil: 1mg/mL  
    SynonymsNSC687852, b-AP15; NSC-687852, b-AP15; NSC 687852, b-AP-15; USP14 Inhibitor III; UCHL5UCH37 Inhibitor II 


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    In Vitro

    In vitro activity:  b-AP15 inhibits the activity of two 19S regulatory-particle-associated deubiquitinases, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14), resulting in accumulation of polyubiquitin. b-AP15 results in a dose-dependent accumulation of the UbG76V-YFP reporter with IC50 of 0.8 μM, indicating impaired proteasome degradation. b-AP15 (1 μM) results in rapid accumulation of polyubiquitinated proteins in human colon carcinoma HCT-116 cells. b-AP15 (2.2 μM) increases the amounts of the cyclin-dependent kinases CDKN1A and CDKNIB and the tumor suppressor TP53 in a dose-dependent manner without altering the amounts of ornithine decarboxylase 1 (ODC1) in HCT-116 cells. b-AP15 (1 μM) results in G2/M phase cell-cycle arrest in HCT-116 cells, consistent with the accumulation of cell-cycle inhibitors. b-AP15 treatment increases the number of hypodiploid cells and is associated with increased amounts of apoptotic markers, including activated caspase-3, caspase-cleaved poly-ADP ribose polymerase (PARP) and cytokeratin-18 (CK18). b-AP15 is more toxic to HCT-116 cells as compared to immortalized epithelial cells (hTERT-RPE1) or peripheral blood mononuclear cells. b-AP15 inhibits deubiquitinating activity using a variety of substrates, including Ub-AMC, Ub-GFP22, ubiquitinated p53-binding protein homolog (HDM2), and K48- and K63-linked ubiquitin tetramer chains. b-AP15 is an inhibitor of the UPS that induced cell death via induction of the lysosomal apoptosis pathway in a cathepsin-D dependent manner. b-AP15 elicits characteristic UPS defects including the accumulation of ubiquitin conjugates and cell cycle inhibitors such as p21, p27 and the tumor suppressor p53. b-AP15 inhibits the deubiquitinase activity of both cysteine DUBs, with USP14 being slightly more sensitive than UCHL5. b-AP15 induces apoptosis in cells over-expressing the anti-apoptotic Bcl-2 protein and in cells lacking the p53 gene. b-AP15 (1 μM) inhibits ATP-induced IL-1β release from LPS-primed peritoneal macrophages. b-AP15 (1 μM) reduces the levels of cell death induced by nigericin treatment in THP-1 cells. b-AP15 (1 μM) significantly reduces the numbers of ASC specks formed after nigericin treatment in LPS-primed THP-1 cells.


    Kinase Assay: For deubiquitinase inhibition assays, 19S regulatory particle (5 nM), 26S (5 nM) UCH-L1 (5 nM), UCH-L3 (0.3 nM), USP2CD (5 nM) USP7CD (5 nM) USP8CD (5 nM) or BAP1 (5 nM) is incubated with DMSO or b-AP15 and monitored the cleavage of ubiquitin-AMC (1,000 nM) using a Wallac VICTOR Multilabel counter or a Tecan Infinite M1000 equipped with 380 nm excitation and 460 nm emission filters.


    Cell Assay: NSC 687852 blocked deubiquitylating activity of USP14 and UCHL5 selectively without inhibiting proteasome activity. NSC 687852 decreased viability in multiple myeloma (MM) cell lines and patient MM cells, inhibited MM cell proliferation even in the presence of bone marrow stroma cells, and overcomed bortezomib resistance. Anti-MM activity of NSC 687852 was associated with growth arrest through downregulating CDC2, CDC25C, and cyclin B1, as well as induction of caspase-dependent apoptosis and activation of unfolded protein response.

    In Vivob-AP15 (5 mg/kg) shows significant antitumor activity in severe combined immunodeficiency (SCID) mice with FaDu squamous carcinoma xenografts. b-AP15 (5 mg/kg) significantly delays tumor onset in mice with HCT-116 colon carcinoma xenografts.  
    Animal modelMice with HCT-116 colon carcinoma xenografts
    Formulation & DosageDissolved in Cremophor EL and polyethylene glycol 400 (1:1); 5 mg/kg; i.p. injection
    References

    Nat Med. 2011 Nov 6;17(12):1636-40; Int J Biochem Cell Biol. 2012 Nov;44(11):1729-38. 


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

    b-AP15

    b-AP15 inhibits the UPS.  2011 Nov 6;17(12):1636-40.

     

    b-AP15

    b-AP15 inhibits deubiquitination by the 19S regulatory particle (RP).  2011 Nov 6;17(12):1636-40.

     

    b-AP15

     b-AP15 inhibits the 19S regulatory particle (RP) deubiquitinases UCHL5 and USP14.  2011 Nov 6;17(12):1636-40.

     

    b-AP15

    b-AP15 inhibits tumor growth in vivo.  2011 Nov 6;17(12):1636-40.

     

    b-AP15

    Inhibition of proteasome activity by bortezomib and b-AP15.  2012 Nov;44(11):1729-38.

     

    b-AP15

    Proteasomal degradation of poly-ubiquitinated proteins.  2012 Nov;44(11):1729-38.


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