Molecular Weight(MW): 443.52
MLN4924 is a small molecule inhibitor of Nedd8 activating enzyme (NAE) with IC50 of 4 nM.
Cited by 26 Publications
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Choose Selective E1 Activating Inhibitors
|Description||MLN4924 is a small molecule inhibitor of Nedd8 activating enzyme (NAE) with IC50 of 4 nM.|
|Features||A mechanism-based inhibitor of NAE, and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme.|
MLN4924 is structurally related to adenosine 59-monophosphate (AMP)—a tight binding product of the NAE reaction. MLN4924 (3 μM) selectively inhibits NAE in HCT-116 cell lysates. MLN4924 (3 μM) inhibits overall protein turnover by <9% in HCT-116 cells. MLN4924 results in a dose-dependent decrease of Ubc12–NEDD8 thioester and NEDD8–cullin conjugates with an IC50 < 0.1 μM in HCT-116 cells, resulting in a reciprocal increase in the abundance of the known CRL substrates CDT1, p27 and NRF2, but not non-CRL substrates. MLN4924 (3 μM) leads cells to accumulate in S-phase as early as 8 hours and results in a significant fraction of cells contained 4N DNA content by 24 hours in HCT-116 cells.  MLN4924 (3 μM) results 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 in ABC DLBCL cells.  MLN4924 (1 μM) triggers DNA replication and inhibit cell proliferation by stabilizing the DNA replication factor Cdt1, a substrate of cullins 1 and 4. MLN4924 (1 μM) , which is sufficient to elevate Cdt1 for 4-5 hours, is found to be sufficient to induce DNA replication and to activate apoptosis and senescence pathways.  MLN4924 treatment induces the characteristics of senescence phenotypes as evidenced by enlarged and flattened cellular morphology and positive staining of senescence-associated β-Gal. MLN4924-induced senescence is associated with cellular response to DNA damage, triggered by accumulation of DNA-licensing proteins CDT1 and ORC1, as a result of inactivation of CRL/SCF E3s. MLN4924-induced senescence is irreversible and coupled with persistent accumulation of p21 and sustained activation of DNA damage response. 
|In vivo||MLN4924 (60 mg/kg) results in a dose- and time-dependent decrease of NEDD8–cullin levels as early as 30 min after administration in HCT-116 tumour-bearing mice, with maximal effect 1–2 hours post-dose. MLN4924 (60 mg/kg) also leads to a dose- and time-dependent increase in the steady state levels of NRF2 and CDT1 in HCT-116 tumour-bearing mice. MLN4924 (60 mg/kg) leads to DNA damage in the tumour indicated by the increased levels of phosphorylated CHK1 in HCT-116 tumour-bearing mice. MLN4924 administered on a BID schedule at 30 mg/kg and 60 mg/kg inhibits tumour growth with T/C values of 0.36 and 0.15, respectively, in mice bearing HCT-116 xenografts.  MLN4924 (60 mg/kg) blocks NAE pathway biomarkers and results in complete tumor growth inhibition in mice bearing human xenograft tumors of ABC- and GCB-DLBCL. MLN4924 (60 mg/kg) results in NF-kappaB pathway inhibition accompanied by tumor regressions in primary human tumor mice models of ABC-DLBCL. |
In vitro E1-activating enzyme assays:A time-resolved fluorescence energy transfer assay format is used to measure the in vitro activity of NAE. The enzymatic reaction, containing 50 μL 50 mM HEPES, pH 7.5, 0.05% BSA, 5 mM MgCl2, 20 μM ATP, 250 μM glutathione, 10 nM Ubc12–GST, 75 nM NEDD8–Flag and 0.3 nM recombinant human NAE enzyme, is incubated at 24 ℃ for 90 min in a 384-well plate, before termination with 25 μL of stop/detection buffer (0.1 M HEPES, pH 7.5, 0.05% Tween20, 20 mM EDTA, 410 mM KF, 0.53 nM Europium-Cryptate-labelled monoclonal Flag-M2-specific antibody and 8.125 μg/mL PHYCOLINK allophycocyanin (XL-APC)-labelled GST-specific antibody. After incubation for 2 hours at 24 ℃, the plate is read on the LJL Analyst HT Multi-Mode instrument using a time-resolved fluorescence method. A similar assay protocol is used to measure other E1 enzymes.
|In vitro||DMSO||88 mg/mL (198.41 mM)|
|Ethanol||88 mg/mL (198.41 mM)|
|In vivo||Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
5% DMSO+30% PEG 300+5% Tween 80+ddH2O
For best results, use promptly after mixing.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
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Clinical Trial Information
|NCT Number||Recruitment||interventions||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT03814005||Recruiting||Drug: Azacitidine|Drug: Pevonedistat||Myelodysplastic Syndromes|Leukemia Myelomonocytic Chronic|Leukemia Myeloid Acute|Renal Insufficiency|Hepatic Impairment||Millennium Pharmaceuticals Inc.|Takeda||July 10 2019||Phase 1|
|NCT03770260||Recruiting||Drug: Ixazomib Citrate|Drug: Pevonedistat||Recurrent Plasma Cell Myeloma|Refractory Plasma Cell Myeloma||National Cancer Institute (NCI)||April 23 2019||Phase 1|
|NCT03772925||Recruiting||Drug: Belinostat|Drug: Pevonedistat||Recurrent Acute Myeloid Leukemia|Recurrent Myelodysplastic Syndrome|Refractory Acute Myeloid Leukemia|Refractory Myelodysplastic Syndrome||National Cancer Institute (NCI)||February 28 2019||Phase 1|
Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.
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