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Purity: ≥98%
Pevonedistat HCl (MLN4924; TAK924), the hydrochloride salt of Pevonedistat, is an inhibitor of Nedd8 (Neural precursor cell expressed, developmentally down-regulated 8) activating enzyme (NAE) with IC50 of 4 nM. Pevonedistat 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. By binding to and inhibiting NAE, Pevonedistat can inhibit tumor cell proliferation and survival. NAE activates Nedd8, an ubiquitin-like (UBL) protein that modifies cellular targets in a pathway that is parallel to but distinct from the ubiquitin-proteasome pathway (UPP).
| ln Vitro |
Pevonedistat (MLN4924) selectively inhibits the closely related enzymes UAE, SAE, UBA6, and ATG7 (IC50=1.5, 8.2, 1.8, and >10 μM, respectively), while being a powerful inhibitor of NAE (half-maximal inhibitory dose, IC50=0.004 μM). Treatment with pevonedistat (MLN4924) reduces total protein turnover in HCT-116 cells grown. Pevonedistat (MLN4924) treatment of HCT-116 cells for 24 hours causes a dose-dependent decrease of NEDD8-cullin conjugates and Ubc12-NEDD8 thioester, with an IC50 < 0.1 μM. This is accompanied by a reciprocal increase in the abundance of known CRL substrates, such as CDT1, p27, and NRF2 (also called NFE2L2), but not non-CRL substrates[1]. Pevonedistat overcomes stroma-mediated resistance by inducing apoptosis in CLL cells. Pevonedistat encourages the expression of Noxa and Bim in CLL cells, which causes the Bcl-2 family members to rebalance in favor of the proapoptotic BH3-only proteins[2]. Pevonedistat (MLN4924) strongly suppresses migration by transcriptionally activating E-cadherin and suppressing MMP-9. It also immediately inhibits cullin 1 neddylation and remarkably decreases proliferation and survival as well as migration in gastric cancer cells in a dose- and time-dependent manner[3].
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| ln Vivo |
Pevonedistat (MLN492410, 30 or 60 mg/kg, sc) reduces NEDD8-cullin levels in normal mouse tissue, as demonstrated in mouse bone marrow cells, and increases NRF2 and CDT1 steady state levels in HCT-116 tumor-bearing animals in a dose- and time-dependent manner. Tumor development is inhibited by pevonedistat (MLN4924), when given on a BID basis at doses of 30 and 60 mg/kg (T/C values of 0.36 and 0.15, respectively)[1].
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| References |
[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]. J. Claire Godbersen, e tal. The Nedd8-Activating Enzyme Inhibitor MLN4924 Thwarts Microenvironment-Driven NF-κB Activation and Induces Apoptosis in Chronic Lymphocytic Leukemia B Cells. [3]. Lan H, et al. Neddylation inhibitor MLN4924 suppresses growth and migration of human gastric cancer cells. Sci Rep. 2016 Apr 11;6:24218 |
| Molecular Formula |
C21H26CLN5O4S
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| Molecular Weight |
479.98
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| CAS # |
1160295-21-5
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| Related CAS # |
Pevonedistat;905579-51-3
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| SMILES |
[H]Cl.O=S(OC[ C@H]1[C@@H](O)C[ C@H](N2C=CC3=C(N[ C@H]4CCC5=C4C=CC=C5)N=CN=C32)C1)(N)=O
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| Synonyms |
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0834 mL | 10.4171 mL | 20.8342 mL | |
| 5 mM | 0.4167 mL | 2.0834 mL | 4.1668 mL | |
| 10 mM | 0.2083 mL | 1.0417 mL | 2.0834 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution 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 stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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Pevonedistat+TNF-αis cytotoxic.Cell Death Discovery 1, Article number: 15034 (2015) |
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Pevonedistat+TNF-αdrives caspase-8 activation and p10 accumulation.Cell Death Discovery 1, Article number: 15034 (2015) |
Combination of pevonedistat and elevated TNF-αis toxic to rats.Cell Death Discovery 1, Article number: 15034 (2015) |
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