MLN4924 (Synonyms: Pevonedistat) |
| Catalog No.GC15086 |
MLN4924 is a potent and selective small-molecule inhibitor of NEDD8-activating enzyme (NAE) (IC50 = 4 nM), 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).
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 905579-51-3
Sample solution is provided at 25 µL, 10mM.
MLN4924 is a potent and selective small-molecule inhibitor of NEDD8-activating enzyme (NAE) (IC50 = 4 nM) [1,2], 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) [2]. MLN4924 has a multifaceted mechanism of action that is characterized by the induction of DNA re-replication and DNA damage, increased oxidative stress, inhibition of NF-B activity, apoptotic cell death, and cellular senescence [3].
MLN4924 Treatment of HCT-116 cells for 24 h resulted in a dose-dependent decrease of Ubc12-NEDD8 thioester and NEDD8-cullin conjugates, with an IC50 < 0.1 µM [2], resulting in a reciprocal increase in the abundance of the known CRL substrates CDT1, p27 and NRF2 (also known as NFE2L2), c-Jun27, HIF1α, cyclin E29, CDC25A, EMI1 (also known as FBXO5) and phosphorylated IκBα, but not non-CRL substrates [2]. MLN4924 treatment of human-tumour-derived cell lines, including HCT-116(colon), Calu-6 (lung), SKOV-3 (ovarian), H460 (lung), DLD-1 (colon), CWR22 (prostate) and OCI-LY19 (lymphoma), resulted in S-phase-defective phenotypes [2]. Potent inhibition of MLN4924 of cell viability was observed across 17 lymphoma cell lines tested in an ATPlite viability assay, with EC50 values of 10 to 244nM [1].
In OCI-Ly10 xenografts, a dose- and time-dependent increase in pIκBα levels was observed after MLN4924 treatment (10, 30, or 60 mg/kg, subcutaneous), with peak elevation occurring 2 hours after dose and levels returning to baseline at 8 hours after dose. A consequence of inhibiting NAE and NF-κB signaling in OCI-Ly10 xenografts was the induction of apoptosis 8 to 12 hours after a single dose of 60 mg/kg MLN4924, as evidenced by detection of cleaved caspase-3 [1]. A single dose of MLN4924 resulted in a dose- and time-dependent decrease of NEDD8-cullin levels as early as 30 min after administration of MLN4924 (10, 30 or 60 mg/kg, subcutaneous), with maximal effect 1-2 h post-dose on HCT-116 tumour-bearing mice [2].
References:
[1]. Milhollen M A, Traore T, Adams-Duffy J, et al. MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-κB-dependent lymphoma[J]. Blood, The Journal of the American Society of Hematology, 2010, 116(9): 1515-1523.
[2]. Soucy T A, Smith P G, Milhollen M A, et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer[J]. Nature, 2009, 458(7239): 732-736.
[3]. Nawrocki S T, Griffin P, Kelly K R, et al. MLN4924: a novel first-in-class inhibitor of NEDD8-activating enzyme for cancer therapy[J]. Expert opinion on investigational drugs, 2012, 21(10): 1563-1573.
| Cell experiment [1]: | |
|
Cell lines |
HCT-116 cells |
|
Preparation Method |
HCT-116 cells grown in 6-well cell-culture dishes were treated with 0.1% DMSO (control) or MLN4924 for 24 h. Whole cell extracts were prepared and analysed by immunoblotting. For analysis of the E2-UBL thioester levels, lysates were fractionated by non-reducing SDS-PAGE and immunoblotted with polyclonal antibodies to Ubc12, Ubc9 and Ubc10. |
|
Reaction Conditions |
0-3µM for 24 hours |
|
Applications |
Treatment of HCT-116 cells with MLN4924 for 24 h resulted in a dose-dependent decrease of Ubc12-NEDD8 thioester and NEDD8-cullin conjugates, with an IC50 < 0.1 µM |
| Animal experiment [1]: | |
|
Animal models |
Female athymic NCR mice |
|
Preparation Method |
All animals were housed and handled in accordance with the Guide for the Care and Use of Laboratory Animals. Mice were inoculated with 2 × 106 HCT-116 cells (or 30-40 mg H522 tumour fragments) subcutaneously in the right flank, and tumour growth was monitored with caliper measurements. When the mean tumour volume reached approximately 200 mm3, animals were dosed subcutaneously with vehicle (10% cyclodextrin) or MLN4924. Inhibition of tumour growth (T/C) was calculated on the last day of treatment. |
|
Dosage form |
subcutaneous injection, once (QD) or twice (BID) daily,30 and 60 mg kg-1 |
|
Applications |
MLN4924 administered on a BID schedule at 30 and 60 mg kg-1 inhibited tumour growth with T/C values of 0.36 and 0.15, respectively |
|
References: |
|
| Cas No. | 905579-51-3 | SDF | |
| Synonyms | Pevonedistat | ||
| Chemical Name | [(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl]methyl sulfamate | ||
| Canonical SMILES | C1CC2=CC=CC=C2C1NC3=NC=NC4=C3C=CN4C5CC(C(C5)O)COS(=O)(=O)N | ||
| Formula | C21H25N5O4S | M.Wt | 443.53 |
| Solubility | ≥ 22.2mg/mL in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
1 mg | 5 mg | 10 mg |
| 1 mM | 2.2546 mL | 11.2732 mL | 22.5464 mL |
| 5 mM | 0.4509 mL | 2.2546 mL | 4.5093 mL |
| 10 mM | 0.2255 mL | 1.1273 mL | 2.2546 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
μL
Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)
Calculation results:
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 as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 20 reference(s) in Google Scholar.)
GLPBIO products are for RESEARCH USE ONLY. Please make sure your review or question is research based.
Required fields are marked with *