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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%
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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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Keywords

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