Home Ubiquitin E1 Activating inhibitor Pevonedistat (MLN4924)

Pevonedistat (MLN4924)

Catalog No.S7109

For research use only.

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

Pevonedistat (MLN4924) Chemical Structure

CAS No. 905579-51-3

Selleck's Pevonedistat (MLN4924) has been cited by 72 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 MVLBcpRqeHKxbHnm[ZJifGm4ZTDhd5NigQ>? M2jnSVczKGi{cx?= MXvBcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKEt3NkKgZ4VtdHNiYX\0[ZIhPzJiaILzJIJ6KEOnbHzUbZRmei2JbH:gZZN{[XluIFXDOVAhRSByLkGwPEDPxE1w M{TLZ|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ2OUCwN|UzLz5{NEmwNFM2OjxxYU6=
U2OS MWHBcpRqfHWvb4KgZZN{[Xl? MnrQO|IhcHK| NWLVR5MySW62aYT1cY9zKGGldHn2bZR6KGGpYXnud5QhcHWvYX6gWVJQWyClZXzsd{Bi\nSncjC3NkBpenNiYomgUXRVKGG|c3H5MEBKSzVyIE2gNE4yPiEQvF2u MYq8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQDN6OEWyNEc,Ojh|OEi1NlA9N2F-
HCT116 MojVRY51cXS3bX;yJIF{e2G7 M4jBTFczKGi{cx?= NXu1ToV2SW62aYT1cY9zKGGldHn2bZR6KGGpYXnud5QhcHWvYX6gTGNVOTF4IHPlcIx{KGGodHXyJFczKGi{czDifUBOXFRiYYPzZZktKEmFNUCgQUAxNjF7IN88UU4> NFvkZVc9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OEO4PFUzOCd-MkizPFg2OjB:L3G+
Caco2 NILEe4hHfW6ldHnvckBie3OjeR?= NGDuSnkyPiCqcoO= MXvJcohq[mm2aX;uJI9nKE6DRT3t[YRq[XSnZDDVZoNtOi2QRVTEPEBkd26sdXfheIlwdiCrbjDoeY1idiCFYXPvNkBk\WyuczDh[pRmeiBzNjDodpMh[nliV3XzeIVzdiCkbH;0JIFv[Wy7c3nzMEBGSzVyIE2gN{41KM7:TT6= NUXsc3Y2RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkmyN|I2PzlpPkK5NlMzPTd7PD;hQi=>
Caco2 MljESpVv[3Srb36gZZN{[Xl? NIT5OFcyPiCqcoO= NHXybndKdmirYnn0bY9vKG:oIF7BSU1u\WSrYYTl[EBW[mOuMj3OSWRFQCClb37qeYdifGmxbjDpckBpfW2jbjDDZYNwOiClZXzsd{Bi\nSncjCxOkBpenNiYomgW4V{fGW{bjDicI91KGGwYXz5d4l{NCCHQ{WwJF0hOy52IN88UU4> NVy1WJJ[RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkmyN|I2PzlpPkK5NlMzPTd7PD;hQi=>
Caco2 M4nTTmN6fG:2b4jpZ4l1gSCjc4PhfS=> MXS3NkBpenN? NF:2c2VEgXSxdH;4bYNqfHliYXfhbY5{fCCqdX3hckBE[WOxMjDj[YxteyCjZoTldkA4OiCqcoOgZpkhVVSWIHHzd4F6NCCLQ{WwJF0hPC52IN88UU4> M1m0UlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ7MkOyOVc6Lz5{OUKzNlU4QTxxYU6=
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 ; Culin 1 / WEE1 / p27 / p-H3 / cyclin B1 ; Cleaved caspase-3 / Cleaved PARP ; pro-apoptotic and anti-apoptotic proteins ; p-c-Jun / c-Jun ; p-H2A / p-CHK2 ; p-AKT / p-mTOR / p-70S6K 28838998 27224919 25782162 21914854 30402022
Immunofluorescence RhoB / VE-cadherin / F-actin 29358211
Growth inhibition assay Cell viability 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 (from reference)

Kinase Assay:[1]
  • 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]
  • 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.
Animal Research:[1]
  • Animal Models: mice bearing HCT-116 xenografts
  • Dosages: 60 mg/kg
  • Administration: Subcutaneously injection

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

Chemical Information

Molecular Weight 443.52
Formula

C21H25N5O4S
CAS No. 905579-51-3
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles C1CC2=CC=CC=C2C1NC3=C4C=CN(C4=NC=N3)C5CC(C(C5)O)COS(=O)(=O)N

In vivo Formulation Calculator (Clear solution)

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Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
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Molarity Calculator

Mass Concentration Volume Molecular Weight

Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04985656 Withdrawn Drug: Pevonedistat|Drug: Decitabine|Drug: Cedazuridine Myelodysplastic Syndromes (MDS) Takeda October 1 2021 Phase 2
NCT04800627 Recruiting Biological: Pembrolizumab|Drug: Pevonedistat Locally Advanced Malignant Solid Neoplasm|Metastatic Malignant Solid Neoplasm|Unresectable Malignant Solid Neoplasm M.D. Anderson Cancer Center March 29 2021 Phase 1|Phase 2
NCT04266795 Active not recruiting Drug: Pevonedistat|Drug: Venetoclax|Drug: Azacitidine Acute Myeloid Leukemia (AML) Takeda October 13 2020 Phase 2
NCT04172844 Active not recruiting Drug: Azacitidine|Drug: Venetoclax|Drug: Pevonedistat Acute Myelogenous Leukemia Medical College of Wisconsin January 13 2020 Phase 1

(data from https://clinicaltrials.gov, updated on 2022-01-17)

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