MLN4924
mRNA synthesis
In vitro transcription of capped mRNA with modified nucleotides and Poly(A) tail
Tyramide Signal Amplification (TSA)
TSA (Tyramide Signal Amplification), used for signal amplification of ISH, IHC and IC etc.
Phos Binding Reagent Acrylamide
Separation of phosphorylated and non-phosphorylated proteins without phospho-specific antibody
Cell Counting Kit-8 (CCK-8)
A convenient and sensitive way for cell proliferation assay and cytotoxicity assay
SYBR Safe DNA Gel Stain
Safe and sensitive stain for visualization of DNA or RNA in agarose or acrylamide gels.
Inhibitor Cocktails
Protect the integrity of proteins from multiple proteases and phosphatases for different applications.
MLN4924是一种有效的和选择性的NEDD8激活酶（NAE）抑制剂，IC50值为4 nM[1]。
MLN4924与AMP竞争结合NAE的核苷酸结合位点。与密切相关的酶UAE、SAE、UBA6和ATG7（IC50值分别为1.5、8.2、1.8和10 μM）相比，MLN4924对NAE具有高选择性。MLN4924对其它利用ATP的酶没有作用。在HCT-116细胞中，MLN4924导致Ubc12-NEDD8硫酯和NEDD8-滞蛋白（cullin）缀合物的减少，从而抑制CRL-泛素化介导的蛋白降解（比如CDT1蛋白），CDT1蛋白的积累会引起细胞周期缺陷。在HCT-116异种移植小鼠中，MLN4924以30 mg/kg和60 mg/kg的剂量显著抑制肿瘤生长，这些剂量的耐受性良好。在H522和Calu-6肺癌异种移植小鼠中，MLN4924也具有抗肿瘤活性[1]。
参考文献：
[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.
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| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 443.53 |
| Cas No. | 905579-51-3 |
| Formula | C21H25N5O4S |
| Solubility | ≥22.18 mg/mL in DMSO; insoluble in H2O; ≥42.2 mg/mL in EtOH |
| 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 |
| SDF | Download SDF |
| Canonical SMILES | C1CC2=CC=CC=C2C1NC3=NC=NC4=C3C=CN4C5CC(C(C5)O)COS(=O)(=O)N |
| 运输条件 | 蓝冰运输或根据您的需求运输。 |
| 一般建议 | 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。溶液形式一般不宜长期储存，请尽快用完。 |
| 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. |
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质量控制和MSDS
- 批次:
化学结构
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