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A-1210477

现货
Catalog No.
B6011
MCL-1抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 2,900.00
现货
5mg
¥ 1,050.00
现货
25mg
¥ 3,000.00
现货

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Background

A-1210477 is an effective and specific MCL-1 inhibitor with an EC50 value below 5 µmol/L [1]. Selectively, it binds to MCL-1 with an affinity of 0.45 nM [2].

MCL-1, an anti-apoptotic Bcl-2 family member, is an anti-apoptotic protein. It is a key regulator of cancer cell survival [3, 4].

In MCL-1-dependent SVEC cells, treatment with A-1210477 at varying doses, induced cell death in a dose-dependent manner. SYTOX Green exclusion and live-cell imaging were used to determine cell viability. In line with increased potency, cell death was more rapidly induced by A-1210477. To examine the selectivity of A-1210477 for targeting Bcl-2 family members, BcL-xL-, BcL-2-, and MCL-1-dependent SVEC cells were treated with A-1210477. A-1210477 only killed MCL-1-dependent cells. Compared with UMI-77, A-1210477 showed greater potency and specificity as an MCL-1 inhibitor, the EC50 value of UMI-77 is 10 µmol/L [1]. In living cells, A-1210477 disrupted BIM/MCL-1 complexes. In MCL-1-dependent cancer cells, A-1210477 induced the hallmarks of mitochondrial apoptosis. In various malignant cell lines, A-1210477 induced apoptosis, synergizing with navitoclax. Data also demonstrate that A-1210477 acted through an on-target mechanism. It appeared as the first BH3 mimetic targeting MCL-1 [2].

The pharmacokinetics of A-1210477 are not favorable for in vivo use [5].

References:
[1].  Lopez J, Bessou M, Riley JS, et al. Mito-priming as a method to engineer Bcl-2 addiction. Nature communications, 2016, 7:10538.
[2].  Besbes S, Mirshahi M, Pocard M, et al. New dimension in therapeutic targeting of BCL-2 family proteins. Oncotarget, 2015, 6(15): 12862.
[3].  Leverson JD, Zhang H, Chen J, et al. Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax). Cell death & disease, 2015, 6(1): e1590.
[4].  Mott JL, Kobayashi S, Bronk SF, et al. mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene, 2007, 26(42): 6133-6140.
[5].  Opferman JT. Attacking cancer's Achilles heel: antagonism of anti-apoptotic BCL-2 family members. FEBS Journal, 2015.

文献引用

1. Bianchetti E, Bates SJ, et al. "Usp9X Regulates Cell Death in Malignant Peripheral Nerve Sheath Tumors." Sci Rep. 2018 Nov 26;8(1):17390. PMID:30478285
2. Campbell KJ, Dhayade S, et al. "MCL-1 is a prognostic indicator and drug target in breast cancer." Cell Death Dis. 2018 Jan 16;9(2):19. PMID:29339815

Chemical Properties

StorageStore at -20°C
M.Wt850.04
Cas No.1668553-26-1
FormulaC46H55N7O7S
Solubility<1.7mg/mL in DMSO
Chemical Name7-(5-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1-yl)phenoxy)methyl)-1,3-dimethyl-1H-pyrazol-4-yl)-1-(2-morpholinoethyl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
SDFDownload SDF
Canonical SMILESCC1=NN(C(COC2=CC=C(N3CCN(S(N(C)C)(=O)=O)CC3)C=C2)=C1C4=CC=CC(C(CCCOC5=CC=CC6=CC=CC=C65)=C7C(O)=O)=C4N7CCN8CCOCC8)C
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]:

结合亲和力试验

使用TR-FRET结合亲和力试验测定化合物对BCL-2、BCL-XL和MCL-1的亲和力。反应体系含4.52 mM磷酸二氢钾,15.48 mM磷酸氢二钾,1 mM EDTA钠,0.05% Pluronic F-68 洗涤剂,50 mM 氯化钠以及1 mM DTT (pH 7.5)。在MCL-1试验中,将GST-标记的MCL-1 (1 nM) 与100 nM f-Bak,1 nM Tb标记的抗GST抗体和化合物于室温下混合60分钟。在Envision酶标仪上,采用340/35 nm激发滤光片以及520/525 (f-Bak) 和495/510 nm (Tb标记的抗GST 抗体)发射滤光片测量样品的荧光。

细胞实验 [1]:

细胞系

H929细胞

制备方法

该化合物可溶于DMSO。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C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 °C可放置数月。

反应条件

0 ~ 30 μM;4小时

实验结果

在H929细胞中,A-1210477选择性地并有效地结合MCL-1,从而呈剂量依赖性地减少MCL-1和BIM免疫沉淀物,其IC50值在较低的μM范围内。

References:

[1]. Leverson JD, Zhang H, Chen J, et al. Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax). Cell death & disease, 2015, 6(1): e1590.

质量控制

化学结构

A-1210477

相关生物数据

A-1210477

相关生物数据

A-1210477