Pevonedistat (MLN4924)

Catalog No.S7109

Pevonedistat (MLN4924) Chemical Structure

Molecular Weight(MW): 443.52

MLN4924 is a small molecule inhibitor of Nedd8 activating enzyme (NAE) with IC50 of 4 nM.

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Cited by 6 Publications

3 Customer Reviews

  • Immunoblot analysis of IKZF1/3 and CRBN levels in MM.1S cells treated with Poma (P, 10 nM) for 16 h, after incubating with MLN4924 (M, 0.2 μM) or DMSO for 48 h

    Leukemia, 2019, 33(1):171-180. Pevonedistat (MLN4924) purchased from Selleck.

    BEL7402 or HepG2 cells were transfected with GFP-tagged Hakai and treated with 0.5% DMSO, 10 μM MG132 and 5 μM MLN4924 (c). Endogenous Ajuba levels were determined by immunoblotting using anti-Ajuba antibody. GAPDH was used as a loading control. Densitometry was performed for quantification, and the ratios of Ajuba and GAPDH are presented.

    J Exp Clin Cancer Res, 2018, 37(1):165. Pevonedistat (MLN4924) purchased from Selleck.

  • (A) Mouse peritoneal macrophages were pretreated with DMSO or MLN4924 for 2 h and then stimulated with LPS or poly(I:C) for the indicated time period. Phosphorylated and total signaling proteins were examined by Western blot analysis.

    J Immunol, 2016, 196(7):3117-23. Pevonedistat (MLN4924) purchased from Selleck.

Purity & Quality Control

Choose Selective E1 Activating Inhibitors

Biological Activity

Description MLN4924 is a small molecule inhibitor of Nedd8 activating enzyme (NAE) with IC50 of 4 nM.
Features A mechanism-based inhibitor of NAE, and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme.
In vitro

MLN4924 is structurally related to adenosine 59-monophosphate (AMP)—a tight binding product of the NAE reaction. MLN4924 (3 μM) selectively inhibits NAE in HCT-116 cell lysates. MLN4924 (3 μM) inhibits overall protein turnover by <9% in HCT-116 cells. MLN4924 results in a dose-dependent decrease of Ubc12–NEDD8 thioester and NEDD8–cullin conjugates with an IC50 < 0.1 μM in HCT-116 cells, resulting in a reciprocal increase in the abundance of the known CRL substrates CDT1, p27 and NRF2, but not non-CRL substrates. MLN4924 (3 μM) leads cells to accumulate in S-phase as early as 8 hours and results in a significant fraction of cells contained 4N DNA content by 24 hours in HCT-116 cells. [1] MLN4924 (3 μM) results in rapid accumulation of pIkappaBalpha, decrease in nuclear p65 content, reduction of nuclear factor-kappaB (NF-kappaB) transcriptional activity, and G(1) arrest, ultimately resulting in apoptosis induction, events consistent with potent NF-kappaB pathway inhibition in ABC DLBCL cells. [2] MLN4924 (1 μM) triggers DNA replication and inhibit cell proliferation by stabilizing the DNA replication factor Cdt1, a substrate of cullins 1 and 4. MLN4924 (1 μM) , which is sufficient to elevate Cdt1 for 4-5 hours, is found to be sufficient to induce DNA replication and to activate apoptosis and senescence pathways. [3] MLN4924 treatment induces the characteristics of senescence phenotypes as evidenced by enlarged and flattened cellular morphology and positive staining of senescence-associated β-Gal. MLN4924-induced senescence is associated with cellular response to DNA damage, triggered by accumulation of DNA-licensing proteins CDT1 and ORC1, as a result of inactivation of CRL/SCF E3s. MLN4924-induced senescence is irreversible and coupled with persistent accumulation of p21 and sustained activation of DNA damage response. [4]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
K562 cells NWnYT4JLWHKxbHnm[ZJifGmxbjDhd5NigQ>? MXS3NkBp NV;LSHNnSW62aYDyc4xq\mW{YYTpeoUh[WO2aY\peJkh[WejaX7zeEBpfW2jbjDLOVYzKGOnbHzzJIFnfGW{IEeyJIhzeyCkeTDD[YxtXGm2ZYKtS4xwKGG|c3H5MEBGSzVyPUCuNVA5KM7:TR?= NEnHO|MzPDlyMEO1Ni=>

... Click to View More Cell Line Experimental Data

In vivo MLN4924 (60 mg/kg) results in a dose- and time-dependent decrease of NEDD8–cullin levels as early as 30 min after administration in HCT-116 tumour-bearing mice, with maximal effect 1–2 hours post-dose. MLN4924 (60 mg/kg) also leads to a dose- and time-dependent increase in the steady state levels of NRF2 and CDT1 in HCT-116 tumour-bearing mice. MLN4924 (60 mg/kg) leads to DNA damage in the tumour indicated by the increased levels of phosphorylated CHK1 in HCT-116 tumour-bearing mice. MLN4924 administered on a BID schedule at 30 mg/kg and 60 mg/kg inhibits tumour growth with T/C values of 0.36 and 0.15, respectively, in mice bearing HCT-116 xenografts. [1] MLN4924 (60 mg/kg) blocks NAE pathway biomarkers and results in complete tumor growth inhibition in mice bearing human xenograft tumors of ABC- and GCB-DLBCL. MLN4924 (60 mg/kg) results in NF-kappaB pathway inhibition accompanied by tumor regressions in primary human tumor mice models of ABC-DLBCL. [2]

Protocol

Kinase Assay:[1]
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In vitro E1-activating enzyme assays:

A time-resolved fluorescence energy transfer assay format is used to measure the in vitro activity of NAE. The enzymatic reaction, containing 50 μL 50 mM HEPES, pH 7.5, 0.05% BSA, 5 mM MgCl2, 20 μM ATP, 250 μM glutathione, 10 nM Ubc12–GST, 75 nM NEDD8–Flag and 0.3 nM recombinant human NAE enzyme, is incubated at 24 ℃ for 90 min in a 384-well plate, before termination with 25 μL of stop/detection buffer (0.1 M HEPES, pH 7.5, 0.05% Tween20, 20 mM EDTA, 410 mM KF, 0.53 nM Europium-Cryptate-labelled monoclonal Flag-M2-specific antibody and 8.125 μg/mL PHYCOLINK allophycocyanin (XL-APC)-labelled GST-specific antibody. After incubation for 2 hours at 24 ℃, the plate is read on the LJL Analyst HT Multi-Mode instrument using a time-resolved fluorescence method. A similar assay protocol is used to measure other E1 enzymes.
Cell Research:[1]
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  • Cell lines: HCT-116 cells
  • Concentrations: 3 μM
  • Incubation Time: 72 hours
  • Method: Cell suspensions are seeded at 3,000–8,000 cells per well in 96-well culture plates and incubated overnight at 37 ℃. MLN4924 are added to the cells in complete growth media and incubated for 72  hours at 37 ℃. Cell number is quantified using the ATPlite assay.
    (Only for Reference)
Animal Research:[1]
+ Expand
  • Animal Models: mice bearing HCT-116 xenografts
  • Formulation: 10% cyclodextrin
  • Dosages: 60 mg/kg
  • Administration: Subcutaneously injection
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 88 mg/mL (198.41 mM)
Ethanol 88 mg/mL (198.41 mM)
Water Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
5% DMSO+30% PEG 300+5% Tween 80+ddH2O
For best results, use promptly after mixing.
20mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 443.52
Formula

C21H25N5O4S

CAS No. 905579-51-3
Storage powder
in solvent
Synonyms

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT03770260 Not yet recruiting Recurrent Plasma Cell Myeloma|Refractory Plasma Cell Myeloma National Cancer Institute (NCI) June 7 2019 Phase 1
NCT03349281 Recruiting Refractory Acute Lymphoblastic Leukemia|Relapsed Acute Lymphoblastic Leukemia Julio Barredo|Takeda|University of Miami June 2019 Phase 1
NCT03770260 Not yet recruiting Recurrent Plasma Cell Myeloma|Refractory Plasma Cell Myeloma National Cancer Institute (NCI) June 7 2019 Phase 1
NCT03349281 Recruiting Refractory Acute Lymphoblastic Leukemia|Relapsed Acute Lymphoblastic Leukemia Julio Barredo|Takeda|University of Miami June 2019 Phase 1
NCT03862157 Not yet recruiting Acute Myeloid Leukemia|Atypical Chronic Myeloid Leukemia BCR-ABL1 Negative|Chronic Eosinophilic Leukemia Not Otherwise Specified|Chronic Myelomonocytic Leukemia|Chronic Neutrophilic Leukemia|Dysplasia|Essential Thrombocythemia|FGFR1 Gene Rearrangement|Myelodysplastic Syndrome|Myelodysplastic/Myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosis|Myelodysplastic/Myeloproliferative Neoplasm Unclassifiable|Myeloid Neoplasm|Myeloproliferative Neoplasm|Myeloproliferative Neoplasm Unclassifiable|Overt Primary Myelofibrosis|PDGFRA Gene Rearrangement|PDGFRB Gene Rearrangement|Polycythemia Vera|Polycythemia Vera Post-Polycythemic Myelofibrosis Phase|Prefibrotic/Early Primary Myelofibrosis M.D. Anderson Cancer Center|National Cancer Institute (NCI) May 31 2019 Phase 1|Phase 2
NCT03813147 Not yet recruiting Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome|Blasts 0.1 Percent or More of Bone Marrow Nucleated Cells|Blasts 5 Percent or More of Bone Marrow Nucleated Cells|Recurrent Acute Myeloid Leukemia|Recurrent High Risk Myelodysplastic Syndrome|Refractory Acute Myeloid Leukemia National Cancer Institute (NCI) May 4 2019 Phase 1

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E1 Activating Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID