A-1210477
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.
A-1210477是MCL-1的有效特异性抑制剂，EC50值低于5 μmol/L[1]。它选择性结合MCL-1，亲和力为0.45 nM [2]。
MCL-1属于抗细胞凋亡Bcl-2家族，是一种抗凋亡蛋白。它是癌症细胞存活的关键调节剂[3,4]。
在MCL-1依赖性的SVEC细胞中，不同剂量的A-1210477以剂量依赖性方式诱导细胞死亡。使用SYTOX和活细胞成像确定细胞活力。与增加的效能一致，A-1210477引起细胞迅速死亡。为了测试A-1210477对Bcl-2家族成员的选择性，在依赖BCL-XL、BCL-2-和MCL-1的SVEC细胞中加入A-1210477， A-1210477仅杀死MCL-1依赖性细胞。作为MCL-1抑制剂，与UMI-77相比，A-1210477表现出更大的效力和特异性，UMI-77的EC50值是10 μmol/ L[1]。在活细胞中，A-1210477扰乱BIM/MCL-1复合物。在MCL-1依赖性癌症细胞中，A-1210477诱导了线粒体凋亡的标志。在各种肿瘤细胞系中，A-1210477诱导细胞凋亡，与navitoclax具有协同性。数据表明，A-1210477通过靶机制发挥作用。它作为第一个BH3模拟物靶向MCL-1 [2]。
A-1210477的药代动力学不支持在体的应用[5]。
参考文献：
[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.
- 1. Kirsteen J. Campbell, Susan M. Mason, et al. "Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function." Cell Death Differ. 2021 Sep;28(9):2589-2600. PMID:33785871
- 2. Kim YJ, Tsang T, et al. "Inhibition of BCL2 family members increases the efficacy of copper chelation in BRAFV600E-driven melanoma." Cancer Res. 2020;canres.1784.2019. PMID:32005716
- 3. Villalobos-Ortiz M, Ryan J, et al. "BH3 profiling discriminates on-target small molecule BH3 mimetics from putative mimetics." Cell Death Differ. 2019 Jul 22. PMID:31332296
- 4. 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
- 5. 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
| Storage | Store at -20°C |
| M.Wt | 850.04 |
| Cas No. | 1668553-26-1 |
| Formula | C46H55N7O7S |
| Solubility | insoluble in DMSO; insoluble in H2O; insoluble in EtOH |
| Chemical Name | 7-(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 |
| SDF | Download SDF |
| Canonical SMILES | CC1=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 | 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]: | |
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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]: | |
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细胞系 |
H929细胞 |
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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。 |
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反应条件 |
0 ~ 30 μM；4小时 |
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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。 |
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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. |
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质量控制和MSDS
- 批次:
化学结构
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