Pevonedistat (MLN4924)

For research use only.

Catalog No.S7109

40 publications

Pevonedistat (MLN4924) Chemical Structure

CAS No. 905579-51-3

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

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10mM (1mL in DMSO) USD 259 In stock
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Selleck's Pevonedistat (MLN4924) has been cited by 40 publications

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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.
Targets
NAE [1]
(Cell-free assay)
4 nM
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 NY\m[Zh2WHKxbHnm[ZJifGmxbjDhd5NigQ>? NVrEcFhtPzJiaB?= NILzNJJCdnSrcILvcIln\XKjdHn2[UBi[3Srdnn0fUBi\2GrboP0JIh2dWGwIFu1OlIh[2WubIOgZYZ1\XJiN{KgbJJ{KGK7IFPlcIxVcXSncj3HcI8h[XO|YYmsJGVEPTB;MD6xNFgh|ryP NXHaZZpKOjR7MECzOVI>

... Click to View More Cell Line Experimental Data
Assay
Methods Test Index PMID
Western blot
Culin 3 / CDT2 / CDT1 / SET8 / p21 / p-p53 / p-CHK1 / p-CHK2 / CHK2 / γH2AX / H2AX / PARP / c-PARP; 

PubMed: 28838998     


Immunoblotting of protein lysates extracted from Cal27 or FaDu cells treated with the indicated doses of pevonedistat for 24 or 48 hrs. Actin is a loading control.

Culin 1 / WEE1 / p27 / p-H3 / cyclin B1; 

PubMed: 27224919     


MLN4924-IR induced G2 arrest and accumulation of WEE1/p21/p27. Subconfluent cells were treated with MLN4924 (DU145 at 200 nM and PC3 at 150 nM) or IR (4 Gy) or MLN4924+IR, followed by IB analysis, using antibodies against cullin1, WEE1, p21, p27, p-H3, t-H3, and cyclin B1, with GAPDH as a loading control. 

Cleaved caspase-3 / Cleaved PARP; 

PubMed: 25782162     


MLN4924 significantly induced apoptosis in SU-DHL-4 and Toledo cells, but not Raji and U937 cells. The four lymphoma cells were treated with MLN4924 at 0.1 and 0.3 μM or DMSO for 48 h, and subjected to immunoblotting using antibodies against cleaved caspase-3 and cleaved PARP with GAPDH as a loading control.

pro-apoptotic and anti-apoptotic proteins; 

PubMed: 25782162     


Effects of MLN4924 on expression of pro-apoptotic and anti-apoptotic proteins. SU-DHL-4 and Toledo cells were treated with MLN4924 at 0.1 and 0.3 μM or DMSO for 48 h, followed by immunoblotting using indicated antibodies against pro-apoptotic (left panel) and anti-apoptotic (right panel) proteins with GAPDH as a loading control.

p-c-Jun / c-Jun; 

PubMed: 21914854     


A and B, The given cell lines were treated with different concentrations of MLN4924 as indicated for 12 h (A) or 1 µM MLN4924 for the indicated times (B).

p-H2A / p-CHK2 ; 

PubMed: 30402022     


HCT116 and HT29 cells were treated with vehicle or 0.3 µM MLN4924 for 12, 24 or 48 h. The expression of p-H2A, T-H2A, p-CHK2, T-CHK2, p21 and p27 was determined by western blot.

p-AKT / p-mTOR / p-70S6K; 

PubMed: 30402022     


HCT116 and HT29 cells were treated with vehicle or 0.3 µM MLN4924 for 12, 24 or 48 h. The expression of p-AKT, p-mTOR and p-70S6K were determined by western blot. GAPDH was used for loading control.

28838998 27224919 25782162 21914854 30402022
Immunofluorescence
RhoB / VE-cadherin / F-actin; 

PubMed: 29358211     


HUVECs were treated overnight with 300 nM MLN4924, 10 ng/ml human TNF-α, or a combination of both. Cells were fixed and stained for RhoB and VE–cadherin, F-actin, and nuclei. Bars, 20 µm.

29358211
Growth inhibition assay
Cell viability; 

PubMed: 27333051     


Viability assays of the indicated melanoma lines and melanocytic PIG1 and PIG3V following treatment with the indicated doses of pevonedistat and expressed as a percentage of control DMSO-treated samples. Data represent the average of three independent experiments ± S.D. 

27333051
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]
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  • Animal Models: mice bearing HCT-116 xenografts
  • Dosages: 60 mg/kg
  • Administration: Subcutaneously injection
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 88 mg/mL (198.41 mM)
Water Insoluble
Ethanol '88 mg/mL
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
Smiles C1CC2=CC=CC=C2C1NC3=C4C=CN(C4=NC=N3)C5CC(C(C5)O)COS(=O)(=O)N

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04266795 Recruiting Drug: Pevonedistat|Drug: Venetoclax|Drug: Azacitidine Acute Myeloid Leukemia (AML) Takeda October 13 2020 Phase 2
NCT04172844 Recruiting Drug: Azacitidine|Drug: Venetoclax|Drug: Pevonedistat Acute Myelogenous Leukemia Ehab L Atallah|Medical College of Wisconsin January 13 2020 Phase 1
NCT03770260 Recruiting Drug: Ixazomib Citrate|Drug: Pevonedistat Recurrent Plasma Cell Myeloma|Refractory Plasma Cell Myeloma National Cancer Institute (NCI) April 23 2019 Phase 1

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID