计算溶液所需的质量、体积或浓度。
| 活性类型 | 活性值-log(M) | 作用机制 | 期刊 | 参考文献(PubMed IDs) |
|---|
有货
为什么选择此级别
Moligand™ 级 ，适用于对基线干扰要求严格的色谱和分析工作流程。
储存与运输
-80℃储存。特低温运输 。请查阅批次 COA 获取详细规格。
质量文档
SDS、COA、产品数据表及规格说明书均可下载。可通过批号查询获取批次 COA。
文献证明
在色谱分析、有机合成和交叉偶联反应领域已被 1 篇同行评审文献引用。
概述
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。
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。
Pevonedistat (MLN4924)是Nedd8激活酶(NAE)的小分子抑制剂，IC50为4 nM。
Information
Pevonedistat (MLN4924) MLN4924 is a small molecule inhibitor of Nedd8 activating enzyme ( NAE ) with IC50 of 4 nM.
In vitro
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.
Cell Data
cell lines：
Concentrations：3 μM
Incubation Time：72 hours
Powder Purity:≥97%
规格
别名
派沃奈司他 (MLN4924)
英文别名
Sulfamic acid, [(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl]methyl ester
规格或纯度
Moligand™, 10mM in DMSO
英文名称
Pevonedistat (MLN4924)
生化机理
MLN4924 是一种小分子 Nedd8 激活酶（NAE）抑制剂，IC50 为 4 nM。
储存条件
-80℃储存
运输条件
特低温运输
作用类型
抑制剂
作用机制
NEDD8 激活酶抑制剂
名称和识别符
分子类型
小分子
Isomeric SMILES
C1CC2=CC=CC=C2[C@H]1NC3=C4C=CN(C4=NC=N3)[C@@H]5C[C@H]([C@H](C5)O)COS(=O)(=O)N
分子量
443.53
Reaxy-Rn
23228808
Reaxys-RN link address
https://www.reaxys.com/reaxys/secured/hopinto.do?context=S&query=IDE.XRN=23228808&ln=
技术文档
高级数据
产品属性
| ALogP | 1.7 |
|---|
关联靶点（人）
NEDD8
Tchem
内华达州8号公路(NEDD8)
(1 活性数据)
UBA3
Tchem
NEDD8活化酶E1催化亚基(NEDD8-activating enzyme E1 catalytic subunit)
(1 活性数据)
NAE1
Tchem
NEDD8活化酶E1调节亚基(NEDD8-activating enzyme E1 regulatory subunit)
(1 活性数据)
化学和物理性质
熔点
98°C
质检证书（CoA,COO,BSE/TSE 和分析图谱)
C of A & Other Certificates(BSE/TSE, COO):
输入批号以搜索分析图谱:
技术文档和文章
How to Map the NF-κB Pathway and Choose Inhibitors: Bringing Inflammatory Transcriptional Output into a “Controllable Range” (Tables A–F)
目录： 技术文章
How to Determine Whether a Protein Is Suitable for Targeted Degradation: From Degradation Pathway and Molecular Design to Mechanism Validation
目录： 技术文章
此产品的引用文献
溶液计算器
常见问题
本产品应如何储存？
请于?80 °C条件下保存。需超低温保存以维持规定的有效期。
「Moligand?」是什么？
「Moligand?」是阿拉丁科学的高端产品线之一，专为多个工作流程中的高纯度应用而设计。与同类工作流程中的标准级别相比，「Moligand?」产品通常具有更严格的规格、更严谨的 QC 以及更强的批间一致性。
本产品如何运输？
本产品采用干冰配冷袋冷冻运输。收货后请立即拆包，并按上述储存条件保存；处理干冰时请戴隔热手套并保持通风。
本产品的 CAS 号、分子式和分子量是多少？
本产品的 CAS 号为 905579-51-3，分子式为 C21H25N5O4S，分子量为 443.53 g/mol。
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