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MLN4924

Cat. No. M2189
MLN4924 Structure
Synonym:

Pevonedistat; MLN-4924; MLN 4924

Size Price Availability Quantity
5mg USD 180 In stock
10mg USD 280 In stock
50mg USD 780 In stock
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Quality Control
Biological Activity

MLN4924 is a potent and selective, first-in-class inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy. MLN4924 (3 μM) inhibits overall protein turnover by <9% in HCT-116 cells. MLN4924 induces an alternative mechanism of action. Treatment of ABC DLBCL cells with MLN4924 resulted 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. Expression of UBA3 A171T is sufficient to decrease MLN4924 sensitivity of naive HCT116 cells, indicating that it is a dominant suppressor of MLN4924-mediated cell death. In vivo administration of MLN4924 to mice bearing human xenograft tumors of ABC- and GCB-DLBCL blocked NAE pathway biomarkers and resulted in complete tumor growth inhibition. In primary human tumor models of ABC-DLBCL, MLN4924 treatment resulted in NF-kappaB pathway inhibition accompanied by tumor regressions. MLN4924 has entered Phase-I trials for cancer therapy now.

Protocol
Cell Experiment
Cell lines HCT-116 cells
Preparation method Cell viability assay. Cell suspensions were seeded at 3,000–8,000 cells per well in 96-well culture plates and incubated overnight at 37℃. Compounds were added to the cells in complete growth media and incubated for 72 h at 37℃. Cell number was quantified using the ATPlite assay (PerkinElmer).
Concentrations 0~100µM
Incubation time 72h
Animal Experiment
Animal models Female athymic NCR Mice bearing HCT-116 xenografts
Formulation 10% cyclodextrin
Dosages 10,30 or 60mg/kg
Administration subcutaneously
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information
Molecular Weight 443.52
Formula C21H25N5O4S
CAS Number 905579-51-3
Purity >99%
Solubility DMSO 10 mg/mL
Storage at -20°C
Customer Product Validations & Biological Datas
Source Oncol Lett (2018). Figure 3. MLN4924
Method immunofluorescence
Cell Lines EC1 and Kyse450 cells
Concentrations 0.0, 0.1, 0.2, 0.3, 0.4, 0.6, 0.8, 1.0 μM
Incubation Time 72 h
Results MLN4924 treatment increased the level of CDT1 and ORC1 proteins in a dose.dependent manner.
Rating
References

A gatekeeper residue for NEDD8-activating enzyme inhibition by MLN4924.
Toth JI, et al. Cell Rep. 2012 Apr 19;1(4):309-16. PMID: 22832224.

NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells.
Lin JJ, et al. Cancer Res. 2010 Dec 15;70(24):10310-20. PMID: 21159650.

MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma.
Milhollen MA, et al. Blood. 2010 Sep 2;116(9):1515-23. PMID: 20525923.

An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer.
Soucy TA, et al. Nature. 2009 Apr 9;458(7239):732-6. PMID: 19360080.

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Keywords: MLN4924, Pevonedistat; MLN-4924; MLN 4924 supplier, inhibitors

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