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MLN4924

现货
Catalog No.
B1036
NAE抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,200.00
现货
5mg
¥ 1,300.00
现货
10mg
¥ 2,100.00
现货
50mg
¥ 5,800.00
现货
100mg
¥ 9,500.00
现货

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Background

MLN4924 is a potent and selective inhibitor of NEDD8-activating enzyme (NAE) with IC50 value of 4nM [1].

MLN4924 binds NAE within the nucleotide-binding site competing with AMP. It is a potent inhibitor of NAE and is selective relative to the closely related enzymes UAE, SAE, UBA6 and ATG7 with IC50 values of 1.5, 8.2, 1.8 and 10μM, respectively. MLN4924 shows no effect to other ATP-using enzymes. In HCT-116 cells, MLN4924 treatment results in a decrease of Ubc12–NEDD8 thioester and NEDD8–cullin conjugates, thus resulting in an inhibition of protein degradation mediated by CRL-ubiquitinylation. CDT1 is one of these proteins. The accumulation of CDT1 can cause cell-cycle defects. In mice bearing HCT-116 xenografts, administrations of MLN4924 at 30mg/kg and 60mg/kg significantly inhibit the tumor growth and these doses are well tolerated. The anti-tumour activity of MLN4924 is also found both in mice bearing H522 lung tumour xenografts and in mice bearing Calu-6 lung carcinoma xenografts [1].

References:
[1] Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, Brownell JE, Burke KE, Cardin DP, Critchley S, Cullis CA, Doucette A, Garnsey JJ, Gaulin JL, Gershman RE, Lublinsky AR, McDonald A, Mizutani H, Narayanan U, Olhava EJ, Peluso S, Rezaei M, Sintchak MD, Talreja T, Thomas MP, Traore T, Vyskocil S, Weatherhead GS, Yu J, Zhang J, Dick LR, Claiborne CF, Rolfe M, Bolen JB, Langston SP. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009 Apr 9;458(7239):732-6.

文献引用

1. Mao H, Tang Z, et al. "Neddylation inhibitor MLN4924 suppresses cilia formation by modulating AKT1." Protein Cell. 2019 Mar 9. PMID:30850948
2. Zhou Q, Li H, et al. "Inhibiting neddylation modification alters mitochondrial morphology and reprograms energy metabolism in cancer cells." JCI Insight. 2019 Feb 21;4(4). pii:121582. PMID:30668548
3. Chen X, Cui D, et al. "AKT inhibitor MK-2206 sensitizes breast cancer cells to MLN4924, a first-in-class NEDD8-activating enzyme (NAE) inhibitor." Cell Cycle. 2018;17(16):2069-2079. PMID:30198810
4. Tan S, Liu F, et al. "CSN6, a subunit of the COP9 signalosome, is involved in early response to iron deficiency in Oryza sativa." Sci Rep. 2016 May 3;6:25485. PMID:27137867
5. Lan H, Tang Z, Jin H, Sun Y. "Neddylation inhibitor MLN4924 suppresses growth and migration of human gastric cancer cells. Sci Rep." 2016 Apr 11;6:24218. PMID:27063292

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt443.53
Cas No.905579-51-3
FormulaC21H25N5O4S
Solubility≥22.2mg/mL in DMSO
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
SDFDownload SDF
Canonical SMILESC1CC2=CC=CC=C2C1NC3=NC=NC4=C3C=CN4C5CC(C(C5)O)COS(=O)(=O)N
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验[1]:

体外E1活化的激酶实验

使用时间分辨荧光能量转移实验来测量NAE的体外活性。酶促反应体系包含50 μl 50 mM HEPES、pH 7.5、0.05% BSA、5 mM MgCl2、20 μM ATP、250 μM谷胱甘肽、10 nM Ubc12-GST、75 nM NEDD8-Flag和0.3 nM重组人NAE酶,在384孔板中24℃孵育90分钟,然后用25 μl终止/检测缓冲液终止反应,缓冲液含有0.1 M HEPES、pH 7.5、0.05% Tween20、20 mM EDTA、410 mM KF、0.53 nM Europium-Cryptate标记的Flag-M2特异性单克隆抗体和8.125 μg/ml的PHYCOLINK蓝色荧光蛋白(XL-APC)标记的GST特异性抗体。在24℃下孵育2小时后,使用时间分辨荧光法在LJL Analyst HT Multi-Mode仪器上读取平板。使用类似的实验方案来测量其他E1酶。

细胞实验: [1]

细胞系

HCT-116细胞

制备方法

溶解度有限,若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。

反应条件

24 h

实验结果

用MLN4924处理HCT-116细胞24小时,以剂量依赖性方式减少Ubc12-NEDD8硫酯和NEDD8-胞质结合物,IC50小于0.1 μM。MLN4924使已知CRL底物CDT1、p27和NRF2的丰度增加。在HCT-116细胞中,观察到的最突出的表型是破坏S期调节导致细胞死亡。到24小时,大多数的细胞含有≥4N的DNA含量。

动物实验: [1]

动物模型

HCT-116荷瘤小鼠

给药剂量

皮下注射每日一次(QD)或每日两次(BID)

实验结果

30 mg/kg和60 mg/kg MLN4924每天一次显著抑制肿瘤生长。此外,MLN4924每天给药一次,治疗两天,然后停止五天,进行三个周期,显著抑制肿瘤生长。所有剂量和方案都具有良好耐受性,在治疗结束时所有剂量组的平均体重减轻小于10%。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

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

质量控制

化学结构

MLN4924

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