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Pevonedistat(TAK924 MLN4924)
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
Pevonedistat(TAK924 MLN4924)图片
CAS NO:905579-51-3
规格:≥98%
包装与价格:
包装价格(元)
5mg电议
10mg电议
25mg电议
50mg电议
100mg电议
250mg电议
500mg电议

产品介绍
理化性质和储存条件
Molecular Weight (MW) 443.52
Formula C21H25N5O4S
CAS No.905579-51-3 (free base);
Storage-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)DMSO:88 mg/mL (198.41 mM)
Water: <1 mg/mL
Ethanol:88 mg/mL (198.41 mM)
SMILES CodeO=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
SynonymsMLN-4924; TAK924; MLN4924; TAK 924; MLN 4924; Pevonedistat; TAK-924
实验参考方法
In Vitro

In vitro activity: Pevonedistat (previously known as MLN-4924 and TAK-924) is a potent and selective small molecule 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). 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.


Kinase Assay: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.


Cell Assay:Cell suspensions are seeded at 3,000–8,000 cells per well in 96-well culture plates and incubated overnight at 37 ℃. MLN4924 are added to the cells in complete growth media and incubated for 72 hours at 37 ℃. Cell number is quantified using the ATPlite assay.

In VivoMLN4924 (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.
Animal modelmice bearing HCT-116 xenografts
Formulation & Dosage10% cyclodextrin;60 mg/kg;Subcutaneously injection
ReferencesNature. 2009 Apr 9;458(7239):732-6