IU1

Alias: IU1; IU-1; IU 1
Cat No.:V1324 Purity: ≥98%
IU1 (IU-1; IU 1) is a cell-permeable, reversible and selective proteasome inhibitor of human USP14 with the potential to be used for treatingneurodegenerative disease.
IU1 Chemical Structure CAS No.: 314245-33-5
Product category: DUB
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product 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.

Biological Activity I Assay Protocols (From Reference)
Targets
Usp14(IC50= 4-5 μM)
ln Vitro
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.
ln Vivo
IU1 prevents ventilator-induced lung injury in rats
Enzyme 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
Animal Protocol
Rats
References
Nature. 2010 Sep 9; 467(7312): 179–184.
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C18H21FN2O
Molecular Weight
300.37
Exact Mass
300.16
Elemental Analysis
C, 71.98; H, 7.05; F, 6.32; N, 9.33; O, 5.33
CAS #
314245-33-5
Appearance
Solid powder
SMILES
CC1=CC(C(CN2CCCC2)=O)=C(C)N1C3=CC=C(F)C=C3
InChi Key
JUWDSDKJBMFLHE-UHFFFAOYSA-N
InChi Code
InChI=1S/C18H21FN2O/c1-13-11-17(18(22)12-20-9-3-4-10-20)14(2)21(13)16-7-5-15(19)6-8-16/h5-8,11H,3-4,9-10,12H2,1-2H3
Chemical Name
1-(1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)-2-(pyrrolidin-1-yl)ethan-1-one
Synonyms
IU1; IU-1; IU 1
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO : 41.67~60 mg/mL ( 138.73~199.75 mM )
Ethanol : ~60 mg/mL
Solubility (In Vivo)
5% DMSO+40% PEG300+5% Tween80+50% ddH2O: 3mg/ml (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 3.3292 mL 16.6461 mL 33.2923 mL
5 mM 0.6658 mL 3.3292 mL 6.6585 mL
10 mM 0.3329 mL 1.6646 mL 3.3292 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

Calculator

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An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?
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Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:
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Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
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Calculation results

Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
             (2) Be sure to add the solvent(s) in order.

Biological Data
  • 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 degradationin 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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