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    IU1
    IU1

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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 #: V1324
    CAS #: 314245-33-5Purity ≥98%

    Description: IU1 (IU-1; IU 1) is a cell-permeable, reversible and selective proteasome inhibitor of human USP14 with the potential to be used for treating neurodegenerative disease. It inhibits USP14 with an IC50 of 4.7 μ M, and shows 25-fold higher selectivity against IsoT. USP14 is a proteasome-associated deubiquitinating enzyme that can inhibit the degradation of ubiquitin-protein conjugates both in vitro and in cells. IU1 prevents ventilator-induced lung injury in rats and can inhibit the catalytic activity of proteasome-associated USP14 in vitro with IC50 < 4 μM. Treatment of cultured cells with IU1 enhanced degradation of several proteasome substrates that have been implicated in neurodegenerative disease. USP14 inhibition accelerated the degradation of oxidized proteins and enhanced resistance to oxidative stress. Enhancement of proteasome activity through inhibition of USP14 may offer a strategy to reduce the levels of aberrant proteins in cells under proteotoxic stress. 

    References: Nature. 2010 Sep 9; 467(7312): 179–184.

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    Molecular Weight (MW)300.37
    FormulaC18H21FN2O
    CAS No.314245-33-5
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 60 mg/mL (199.8 mM) 
    Water:<1 mg/mL
    Ethanol: 60 mg/mL (199.8 mM) 
    SMILES Code CC1=CC(C(CN2CCCC2)=O)=C(C)N1C3=CC=C(F)C=C3
    Synonyms IU1; IU-1; IU 1


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    In Vitro

    In vitro activity: IU1 is a cell-permeable, reversible and selective proteasome inhibitor of human USP14 with IC50 of 4.7 μ M, it is 25-fold more selective against IsoT. USP14 is a proteasome-associated deubiquitinating enzyme that can inhibit the degradation of ubiquitin-protein conjugates both in vitro and in cells. IU1 can inhibit the catalytic activity of proteasome-associated USP14 in vitro with IC50 < 4 μM. Treatment of cultured cells with IU1 enhanced degradation of several proteasome substrates that have been implicated in neurodegenerative disease. USP14 inhibition accelerated the degradation of oxidized proteins and enhanced resistance to oxidative stress. Enhancement of proteasome activity through inhibition of USP14 may offer a strategy to reduce the levels of aberrant proteins in cells under proteotoxic stress. IU1 binds specifically to the activated form of USP14. IU1 can potentially inhibit USP14 by preventing its docking on the proteasome, exhibiting little or no activity toward 8 other DUBs, IsoT, UCH37, BAP1, UCH-L1, UCH-L3, USP15, USP2, USP7. USP14 inhibition is rapidly established upon addition of IU1 and rapidly reversed upon its removal. IU1 inhibits USP14 induced chain trimming and decreases electrophoretic mobility of Ub-CCNB species. IU1 enhances proteasomal degradation of Ub-CCNB in the presence of USP14. IU1 promots degradation of tau and depletes TDP-43, ATXN3, and glial fibrillary acidic protein (GFAP) in proteotoxic mechanisms.


    Kinase Assay: Screening is conducted at the ICCB-Longwood screening facility. 10 μL of recombinant USP14 protein are dispensed into each well of a 384-well low volume plate in duplicate, using a Wellmate plate dispenser. 33.3 nL of compound from the library are pin-transferred into the wells using a Seiko pin transfer robotic system, followed by pre-incubation for about 30 min. The last two columns of each plate are used for positive and negative controls for the assay. To initiate the enzyme reaction, 10 μL of VS-proteasome plus Ub-AMC mixture are added to each well, using a Wellmate dispenser. Samples are then incubated for another 45 min. Ub-AMC hydrolysis is measured at Ex355/Em460 using an Envision plate reader. The final concentrations of USP14, VS-proteasome and Ub-AMC are 15 nM, 1 nM and 0.8 μM, respectively. The final concentration of test compound is approximately 17 μM. Enzymes and substrates are prepared in Ub-AMC assay buffer (50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 1 mM ATP, 5 mM MgCl2, 1 mM DTT, and 1 mg/Ml ovalbumin). 


    Cell Assay: MTT assay

    In Vivo IU1 prevents ventilator-induced lung injury in rats
    Animal model Rats
    Formulation & Dosage
    ReferencesNature. 2010 Sep 9; 467(7312): 179–184.


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

    IU1

    IU1 inhibits human Usp14 specifically and reversibly.  2010 Sep 9;467(7312):179-84. 

    IU1

    IU1 inhibits chain trimming and stimulates substrate degradation in vitro.  

    IU1

    IU1 inhibits chain trimming and stimulates substrate degradation in vitro.  2010 Sep 9;467(7312):179-84. 

     

    IU1

    IU1 enhances proteasomal degradation in cells.  

    IU1

    IU1 alleviates cytotoxicity induced by oxidative 


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