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MLN2238

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Catalog No.
A4008
20S蛋白酶体β5位点抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,100.00
现货
5mg
¥ 900.00
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10mg
¥ 1,200.00
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50mg
¥ 3,500.00
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100mg
¥ 6,000.00
现货

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Background

MLN2238 is a potent reversible inhibitor that inhibits specific β5 site of the 20S proteasome with IC50 value of 3.4 nM and Ki value of 0.93 nM.[1]    
MLN2238, an N-capped dipeptidyl leucine boronic acid , preferentially bound to and inhibited the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with an IC50 value of 3.4 nM (Ki value of 0.93 nM). As the concentration increased, it also inhibited the caspase-like (β1) with IC50 value of 31 nM and trypsin-like (β2) proteolytic sites with IC50 value of 3,500 nM. The clinical studies in the model of both solid-tumor and hematological xenograft have demonstrated preclinical antitumor activity. Comparing to bortezomib, MLN2238 showed the activity in pharmacokinetics, pharmacodynamics and antitumor. It is believed that the activation of caspases, the p53 pathway, and endoplasmic reticulum stress and inhibition of NF-κB are related to MLN2238-induced MM cell death. [1,2]        
MLN2238 inhibited growth and triggers apoptosis in MM cells resistant to conventional and bortezomib therapies without affecting the viability of normal cells [2]. MLN2238 has significant cytotoxic activity in RSCL and RRCL preclinical models. Although BTZ and MLN2238 have similar reversible proteasome inhibition, the proteasome dissociation half-life (t1/2) of MLN2238 was found to be approximately sixfold faster than BTZ (t1/2 of 18 vs. 110min, respectively) while has the similar LD50 values to BTZ in a variety of cultured mammalian cancer cell lines. MLN2238 is approximately two to three times more potent than BTZ in lymphoma cell models. The IC50 of MLN2238 was 2.5 nmol/l in contrast to 7.5nmol/l of BTZ in Raji parental cells. [3]
In many mouse models of hematologic malignancies, such as tumor xenograft models which derived from a human lymphoma cell line and primary human lymphoma tissue, and genetically engineered mouse models of plasma cell malignancies, the result showed the antitumor activity of MLN2238.[4]
References:
1.Kupperman E, Lee EC, Cao Y, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Research, 2010, 70 (5): 1970-80.
2.Tian Z, Zhao J, Tai Y, et al. Investigational agent MLN9708/2238 targets tumor-suppressor miR33b in MM cells. Blood, 2012, 120 (19): 3958-3967
3.Gu JJ,  Hernandez-Ilizaliturri FJ, Mavis C, et al. MLN2238, a proteasome inhibitor, induces caspase-dependent cell death, cell cycle arrest, and potentiates the cytotoxic activity of chemotherapy agents in rituximab-chemotherapy-sensitive or rituximab-chemotherapy-resistant B-cell lymphoma preclinical models. ANTI-CANCER DRUGS, 2013, 24 (10): 1030-1038.
4.Lee EC, Fitzgerald M, Bannerman B, et al. Antitumor Activity of the Investigational Proteasome Inhibitor MLN9708 in Mouse Models of B-cell and Plasma Cell Malignancies. CLINICAL CANCER RESEARCH, 2011, 17 (23): 7313-7323.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt361
Cas No.1072833-77-2
FormulaC14H19BCl2N2O4
Solubility≥16.8 mg/mL in DMSO, ≥103 mg/mL in EtOH with ultrasonic, <2.26 mg/mL in H2O
Chemical Name[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]butanoyl]amino]-3-methylbutyl]boronic acid
SDFDownload SDF
Canonical SMILESB(C(CC(C)C)NC(=O)CNC(=O)C1=C(C=CC(=C1)Cl)Cl)(O)O
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]:

激酶实验

采用含10%胎牛血清和1% Penicillin/Streptomycin的MEM培养基培养Calu-6细胞。于实验开始的前1天,按每孔1 × 104个细胞将细胞加入到384孔板中。按照说明书指示加入荧光酶素和 Proteasome-Glo检测试剂,观察糜蛋白酶样底物Suc-LLVY-aminoluciferin水解,测定蛋白酶体活性。使用LEADseeker设备测定荧光值。

细胞实验 [1]:

细胞系

Calu-6细胞

制备方法

在DMSO中的溶解度大于10 mM。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

≤ 10 nM;1小时

实验结果

MLN2238抑制Calu-6细胞,其IC50值为9.7 nM。

动物实验 [2]:

动物模型

携带DP54-Luc肿瘤的NOD-SCID小鼠

给药剂量

11 mg/kg;静脉注射;每周2次,持续17天

实验结果

Bortezomib和MLN2238均降低肿瘤负荷(T/C值分别为0.48和0.22)。

其它注意事项

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]. Kupperman E, Lee EC, Cao Y, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Research, 2010, 70 (5): 1970-80.

[2]. Lee EC, Fitzgerald M, Bannerman B, et al. Antitumor Activity of the Investigational Proteasome Inhibitor MLN9708 in Mouse Models of B-cell and Plasma Cell Malignancies. CLINICAL CANCER RESEARCH, 2011, 17 (23): 7313-7323.

生物活性

描述 MLN2238是20S蛋白酶体胰凝乳蛋白酶样蛋白水解位点(β5)的抑制剂,IC50和Ki值分别为3.4 nM和0.93 nM,也是caspase样(β1)和胰蛋白酶样(β2)蛋白水解位点的抑制剂,IC50值分别为31 nM和3500 nM。
靶点 chymotrypsin-like proteolytic (β5) site of the 20S proteasome caspase-like (β1) proteolytic sites proteasome trypsin-like (β2) proteolytic sites proteasome      
IC50 3.4 nM (Ki=0.93 nM) 31 nM 3500 nM      

质量控制

化学结构

MLN2238