1. Metabolic Enzyme/Protease
  2. NEDD8-activating Enzyme

MLN4924 (Synonyms: Pevonedistat)

Cat. No.: HY-70062 Purity: 98.00%
Handling Instructions

MLN4924 is a potent and selective NEDD8-activating enzyme (NAE) inhibitor with an IC50 of 4.7 nM.

For research use only. We do not sell to patients.

MLN4924 Chemical Structure

MLN4924 Chemical Structure

CAS No. : 905579-51-3

Size Price Stock Quantity
10 mM * 1 mL in DMSO USD 117 In-stock
Estimated Time of Arrival: December 31
1 mg USD 60 In-stock
Estimated Time of Arrival: December 31
5 mg USD 120 In-stock
Estimated Time of Arrival: December 31
10 mg USD 180 In-stock
Estimated Time of Arrival: December 31
50 mg USD 540 In-stock
Estimated Time of Arrival: December 31
100 mg USD 960 In-stock
Estimated Time of Arrival: December 31
200 mg USD 1680 In-stock
Estimated Time of Arrival: December 31
500 mg   Get quote  
1 g   Get quote  

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Customer Review

Other Forms of MLN4924:

    MLN4924 purchased from MCE. Usage Cited in: Elife. 2018 Aug 1;7. pii: e38430.

    H9 hESC are treated with increasing concentrations of Thalidomide, Lenalidomide, Pomalidomide, or DMSO as a control. Following 24 h of incubation, SALL4 and GAPDH protein levels are assessed by western blot analysis.

    MLN4924 purchased from MCE. Usage Cited in: Elife. 2018 Aug 1;7. pii: e38430.

    Kelly cells are treated with increasing concentrations of Thalidomide and co-treated with 5 μM Bortezomib, 5 μM MLN4924, 0.5 μM MLN7243, or DMSO as a control. Following 24 h incubation, SALL4 and GAPDH protein levels are assessed by western blot analysis.

    MLN4924 purchased from MCE. Usage Cited in: Nat Commun. 2017 May 22;8:15398.

    HEK293T cells are treated with 50 μg/mL Cycloheximide and increasing concentrations of Lenalidomide, Thalidomide or with DMSO, and cells are incubated for 6 h. ZFP91 and GAPDH levels are detected using anti-ZFP91 or anti-GAPDH immunoblotting.

    MLN4924 purchased from MCE. Usage Cited in: Elife. 2016 Apr 11;5. pii: e14087.

    Fbxo21-/- RAW264.7 cells are transfected with indicated amounts (0, 1 or 5 μg) Fbxo21-Myc and equal amounts of K29O-Ub-HA vectors for 48 hr, and then infected with VSV (MOI = 1) or HSV-1 (MOI = 5) for 2 hr in the presence or absence of MLN-4924 (10 nM). Then polyubiquitinated ASK1 is examined by immunoblot (IB) against HA after immuneprecipitations (IP).

    MLN4924 purchased from MCE. Usage Cited in: Ann Hematol. 2014 Sep;93(9):1499-508.

    MLN4924-induced p21 high expression eliminates the cell cycle promotion effect of BM-MSCs on Reh cells. a Western blot analysis of p21, skp2, and bax expression in Reh cells treated by different concentration of MLN4924. b Under the treatment of 25 nM IDA, western blot analysis of p21 and skp2 expressions in Reh cells cultured with or without BM-MSCs in the presence of different concentrations of MLN4924 (0, 300, 700 nM). c Under the treatment of 250 nM VP16, western blot analysis of p21 and skp

    MLN4924 purchased from MCE. Usage Cited in: Technol Cancer Res Treat. 2016 Aug;15(4):527-34.

    MLN4924 induces accumulation of SCF E3 ligase substrates. Subconfluent cells are treated with MLN4924 (50 nM) or radiation (6 Gy) alone or in combination for 24 hours, followed by immunoblotting (IB) analysis using indicated antibodies.

    MLN4924 purchased from MCE. Usage Cited in: Oncotarget. 2016 Jun 14;7(24):35643-35654.

    MLN4924 induces apoptosis is caspase dependent. BMDCs are cultured with MLN4924. Total cellular protein extracts are prepared and subjected to immunoblotting by using A. anti-PARP, anti-caspase-3, anti-caspase-7 antibodies and B. anti-cleaved PARP, anti-cleaved-caspase-3, anti-cleaved-caspase-7 antibodies. C. Caspase-3 activity is examined by caspase activity kit. D. Immunoblotting analysis is performed for erk, p-erk, cyclin D1 and cyclin D3 expression.

    MLN4924 purchased from MCE. Usage Cited in: Oncotarget. 2016 Oct 4;7(40):66087-66099.

    MLN4924 increases the stability of RORα. MLN4924 increases the half-life of RORα. U2OS cells are transiently transfected with plasmids expressing the Flag-RORα. At 24 h after transfection, MLN4924 (1 μM) or DMSO are added into respective cell culture media. 24 h later, cells are treated with Cycloheximide (CHX) for 0, 3, 6, 4, 9 and 12 h. Equal amounts of whole cell lysates are analyzed by Western blot with a Flag antibody (M2). Actin is used as an internal control.

    MLN4924 purchased from MCE. Usage Cited in: Oncotarget. 2017 Sep 23;8(49):86395-86409.

    Immunofluorescence results, showing that ROC1, DCAF1, DDB1, and TET1 knockdown, and treatment with MLN4924 leads to the reduction of 5hmC levels in A2780 cells. A2780 cells transfected with siNC, siROC1, siDCAF1, siDDB1 or siTET1 and treatment with MLN4924 are subjected to immunofluorescence analysis with antibodies to the indicated protein.

    MLN4924 purchased from MCE. Usage Cited in: Oncotarget. 2017 Oct 12;8(57):97178-97186.

    After 4 hours 1 µM MLN4924 treatment, lysates from 293T cells stably expressing either Flag or Flag-FBXW8 are immunoprecipitated with anti-FLAG M2 resin. Bound proteins are eluted with FLAG peptide, and all separated cell lysate components are resolved on 10% SDS-PAGE gel, stained by Coomassie Brilliant or subjected to immunoblotting with the indicated antibodies.

    MLN4924 purchased from MCE. Usage Cited in: Cancer Chemother Pharmacol. 2018 Jun;81(6):1083-1093.

    786-0 and ACHN cells are treated with MLN4924 (0.5 μM or 1 μM).γ-H2AX is detected by immunoblotting analysis.

    MLN4924 purchased from MCE. Usage Cited in: Int J Med Sci. 2018 Apr 3;15(7):674-681.

    NB4 cells are treated with MLN4924 (0, 20, 40 and 80 nM) for 0, 24, 48 and 72 hours, and the protein levels of cullin1 are detected by western blotting, with β-actin used as loading control.

    MLN4924 purchased from MCE. Usage Cited in: Nat Commun. 2018 Sep 18;9(1):3801.

    Trophozoites (3D7) are subjected to the indicated treatment for 6 h before analysis of ubiquitinated proteins. Samples treated with MLN4924 are incubated for an additional 3 h prior to DHA treatment. Blots are representative of 3-4 independent experiments.

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    • Biological Activity

    • Protocol

    • Technical Information

    • Purity & Documentation

    • References

    Description

    MLN4924 is a potent and selective NEDD8-activating enzyme (NAE) inhibitor with an IC50 of 4.7 nM.

    IC50 & Target

    IC50: 4.7 nM (NAE)[1]

    In Vitro

    MLN4924 is a potent inhibitor of NAE, and is selective relative to the closely related enzymes UAE, SAE, UBA6 and ATG7 (IC50=1.5, 8.2, 1.8 and >10 μM, respectively) when evaluated in purified enzyme assays that monitor the formation of E2-UBL thioester reaction products. MLN4924 selectively inhibits NAE activity compared to the closely related ubiquitin-activating enzyme (UAE, also known as UBA1) and SUMO-activating enzyme (SAE; a heterodimer of SAE1 and UBA2 subunits), in purified enzyme and cellular assays. MLN4924 exhibits potent cytotoxic activity against a variety of human tumour-derived cell lines[1].

    In Vivo

    MLN4924 (sc, 10 mg/kg, 30 mg/kg, or 60 mg/kg) inhibits the NEDD8 pathway resulting in DNA damage in Mice bearing HCT-116 xenografts[1].Pevonedistat (sc, 120 mg/kg) and TNF-α (10 μg/kg) synergistically cause liver damage in SD rats[2].

    Clinical Trial
    Solvent & Solubility
    In Vitro: 

    DMSO : ≥ 50 mg/mL (112.73 mM)

    *"≥" means soluble, but saturation unknown.

    Preparing
    Stock Solutions
    Concentration Solvent Mass 1 mg 5 mg 10 mg
    1 mM 2.2547 mL 11.2734 mL 22.5469 mL
    5 mM 0.4509 mL 2.2547 mL 4.5094 mL
    10 mM 0.2255 mL 1.1273 mL 2.2547 mL
    *Please refer to the solubility information to select the appropriate solvent.
    In Vivo:
    • 1.

      Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in saline)

      Solubility: ≥ 2.5 mg/mL (5.64 mM); Clear solution

    • 2.

      Add each solvent one by one:  10% DMSO    90% corn oil

      Solubility: ≥ 2.5 mg/mL (5.64 mM); Clear solution

    • 3.

      Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% saline

      Solubility: ≥ 2.5 mg/mL (5.64 mM); Clear solution

    References
    Cell Assay
    [1]

    HCT-116 cells grown in 6-well cell-culture dishes are treated with 0.1% DMSO (control) or 0.3 μM MLN4924 for 24 h. Whole cell extracts are prepared and analysed by immunoblotting. For analysis of the E2-UBL thioester levels, lysates are fractionated by non-reducing SDS-PAGE and immunoblotted with polyclonal antibodies to Ubc12, Ubc9 and Ubc10. For analysis of other proteins, lysates are fractionated by reducing SDS-PAGE and probed with primary antibodies as follows: mouse monoclonal antibodies to CDT1, p27, geminin, ubiquitin, securin/PTTG and p53 or rabbit polyclonal antibodies to NRF2, Cyclin B1 and GADD34[1].

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [1][2]

    Mice[1]
    Mice bearing HCT-116 tumours of 300-500 mm3 are administered a single MLN4924 dose (of 10, 30 or 60 mg/kg), and tumors are excised at various time-points over the subsequent 24 h period. The relative levels of NEDD8-cullin and NRF2 are estimated by quantitative immunoblot analysis using Alexa680-labelled anti-IgG as the secondary antibody. The statistical difference between the groups for NEDD8-cullin inhibition is determined using the Kruskal-Wallis test. For the analysis of CDT1 and phosphorylated CHK1 (Ser317) levels in tumour sections, formalin-fixed, paraffin-embedded tumour sections are stained with the relevant antibodies, amplified with HRP-labelled secondary antibodies and detected with the ChromoMap DAB Kit. Slides are counterstained with haematoxylin. Images are captured using an Eclipse E800 microscope and Retiga EXi colour digital camera and processed using Metamorph software. CDT1 and phosphorylated CHK1 levels are expressed as a function of the DAB signal area.
    Rats[2]
    Ten-week-old male Sprague-Dawley rats are used. Across two studies, a total of eight animals in each group are dosed with vehicle, TNF-α, MLN4924, or MLN4924+TNF-α. Animals are first intravenously administered either vehicle (1×PBS) or 10 μg/kg TNF-α. One hour later, they are subcutaneously administered vehicle (20% sulfobutyl ether beta-cyclodextrin in 50 mM citrate buffer, pH 3.3) or 120 mg/kg MLN4924. Scheduled euthanasia occurred 24 h postdose. Unscheduled euthanasia is performed when animals exhibited moribund conditions. Serum is collected at necropsy and analyzed by Idexx Laboratories for serum chemistry markers of liver damage. Additionally, the livers from five animals in each group are removed, separated into two sections and either frozen at -80°C for subsequent protein analysis or fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned at 4-6 μm, mounted on glass slides, stained with hematoxylin and eosin, and analyzed with an Olympus BX51 light microscope for histopathology assessment. Microscopic findings are recorded in concordance with the standardized nomenclature for classifying lesions within the livers of rats.

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References
    Molecular Weight

    443.52

    Formula

    C₂₁H₂₅N₅O₄S

    CAS No.

    905579-51-3

    SMILES

    O=S(OC[[email protected]@H]1C[[email protected]@H](N2C3=NC=NC(N[[email protected]]4CCC5=C4C=CC=C5)=C3C=C2)C[[email protected]@H]1O)(N)=O

    Storage
    Powder -20°C 3 years
      4°C 2 years
    In solvent -80°C 6 months
      -20°C 1 month
    Shipping

    Room temperature in continental US; may vary elsewhere

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    Product Name:
    MLN4924
    Cat. No.:
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    Cat. No.: HY-70062