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Pevonedistat

Catalog No. T6332 CAS 905579-51-3

Synonyms: MLN4924

MLN4924 is an effective and specific small molecule NEDD8-activating enzyme (NAE) inhibitor (IC50: 4.7 nM).

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Pevonedistat, CAS 905579-51-3

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Purity: 98%

Biological Description

Chemical Properties

Storage & Solubility Information

Description	MLN4924 is an effective and specific small molecule NEDD8-activating enzyme (NAE) inhibitor (IC50: 4.7 nM).
Targets&IC50	NAE:4.7 nM
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].
Kinase Assay	Bcl-2 Binding affinity calculation: A predicted binding affinity for Obatoclax binding to BCL-2 is calculated using the SIE scoring function. [4] As a control in determining the reliability of the calculation, predicted binding affinities Ki) are calculated for a set of 12 small molecules with experimentally measured binding affinities to BCL-2.
Cell Research	MLN4924 is dissolved in DMSO and stored, and then diluted with appropriate medium before use[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].

Synonyms	MLN4924
Molecular Weight	443.52
Formula	C21H25N5O4S
CAS No.	905579-51-3

Storage

Powder: -20°C for 3 years

In solvent: -80°C for 2 years

Solubility Information

DMSO: 125 mg/mL (281.83 mM）, Need ultrasonic

( < 1 mg/ml refers to the product slightly soluble or insoluble )

References and Literature

1. Soucy TA, et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009 Apr 9;458(7239):732-6. 2. Wolenski, F., Fisher, C., Sano, T., Wyllie, S., Cicia, L., & Gallacher, M. et al. (2015). The NAE inhibitor pevonedistat (MLN4924) synergizes with TNF-α to activate apoptosis. Cell Death Discovery, 1(1). doi: 10.1038/cddiscovery.2015.34 3. Fu Z, Liao W, Ma H, et al. Inhibition of neddylation plays protective role in lipopolysaccharide-induced kidney damage through CRL-mediated NF-κB pathways[J]. Am J Transl Res. 2019, 11(5): 2830-2842. 4. Chen S M, Lin T K, Tseng Y Y, et al. Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21[J]. Cancer medicine. 2018 Aug;7(8):3988-4003. 5. Qin Z, Hu H, Sun W, et al. miR-224-5p Contained in Urinary Extracellular Vesicles Regulates PD-L1 Expression by Inhibiting Cyclin D1 in Renal Cell Carcinoma Cells. Cancers . 2021, 13, 618[J]. 2021.

Citations

1. Qin Z, Hu H, Sun W, et al. miR-224-5p Contained in Urinary Extracellular Vesicles Regulates PD-L1 Expression by Inhibiting Cyclin D1 in Renal Cell Carcinoma Cells. Cancers. 2021 Feb 4;13(4):618. doi: 10.3390/cancers13040618. 2. Hussain M, Lu Y, Tariq M, et al. A small-molecule Skp1 inhibitor elicits cell death by p53-dependent mechanism. Iscience. 2022, 25(7): 104591. 3. Chen S M, Lin T K, Tseng Y Y, et al. Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21. Cancer Medicine. 2018 Aug;7(8):3988-4003 4. Fu Z, Liao W, Ma H, et al. Inhibition of neddylation plays protective role in lipopolysaccharide-induced kidney damage through CRL-mediated NF-κB pathways. Am J Transl Res. 2019, 11(5): 2830-2842

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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 add μL PEG300， mix and clarify, next add μL Tween 80，mix and clarify, next add μL ddH₂O, mix and clarify.

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Please see Inhibitor Handling Instructions for more frequently ask questions. Topics include: how to prepare stock solutions, how to store products, and cautions on cell-based assays & animal experiments, etc.

Keywords

Pevonedistat 905579-51-3 Metabolism Ubiquitination E1/E2/E3 Enzyme NEDD8 NEDD8-activating Enzyme MLN-4924 Inhibitor MLN 4924 MLN4924 inhibit NAE inhibitor

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