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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 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.
| Targets |
Usp14(IC50= 4-5 μM)
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| 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.
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| ln Vivo |
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| 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).
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| Cell Assay |
MTT assay
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| Animal Protocol |
Rats
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| References |
| Molecular Formula |
C18H21FN2O
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| Molecular Weight |
300.37
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| Exact Mass |
300.163
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| Elemental Analysis |
C, 71.98; H, 7.05; F, 6.32; N, 9.33; O, 5.33
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| CAS # |
314245-33-5
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| Related CAS # |
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| PubChem CID |
675434
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
437.0±45.0 °C at 760 mmHg
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| Flash Point |
218.1±28.7 °C
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| Vapour Pressure |
0.0±1.0 mmHg at 25°C
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| Index of Refraction |
1.585
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| LogP |
4.07
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
22
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| Complexity |
389
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=CC(C(CN2CCCC2)=O)=C(C)N1C3=CC=C(F)C=C3
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| InChi Key |
JUWDSDKJBMFLHE-UHFFFAOYSA-N
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| 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
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| Chemical Name |
1-(1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)-2-(pyrrolidin-1-yl)ethan-1-one
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : 41.67~60 mg/mL ( 138.73~199.75 mM )
Ethanol : ~60 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (5.56 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.67 mg/mL (5.56 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1.67 mg/mL (5.56 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 5% DMSO+40% PEG300+5% Tween80+50% ddH2O: 3mg/ml |
| 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.
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.
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IU1 inhibits chain trimming and stimulates substrate degradationin vitro.Nature.2010 Sep 9;467(7312):179-84. |
IU1 enhances proteasomal degradation in cells.
IU1 alleviates cytotoxicity induced by oxidative |
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