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PR-619

现货
Catalog No.
A8212
去泛素化酶(DUBs)抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 800.00
现货
5mg
¥ 400.00
现货
25mg
¥ 1,000.00
现货
100mg
¥ 2,800.00
现货

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Background

(2,6-diamino-5-thiocyanatopyridin-3-yl) thiocyanate, also designated as PR-619, is a broad-range reversible and cell-permeable inhibitor of deubiquitylating enzyme (DUB)[1][2][3], potently suppresses the activity of almost all cysteine protease DUBs[4], but shows selectivity toward DUBs over other proteases, such as calpain 1, or cathepsins[3]. PR-619 induces (tumor) cell death with EC50 values in the low micromolar range [1].
Deubiquitylating enzyme (DUB), also called ubiquitin isopeptidase or deubiquitinating proteins, performs deubiquitination of target proteins. Ubiquitination, followed by proteasomal degradation, is a process of ubiquitin proteasome system (UPS). Failure of the ubiquitin proteasome system (UPS) and/or the autophagy pathway may result in aggregation of proteins, a pathological hallmark of many neurodegenerative diseases [2].
In OLN-t40 cells, 7-10 μM as the concentration range for PR-619 to exert its cytotoxicity was suggested, half maximal cytotoxicity was observed after a 24h-treatment with 9-10 μM PR-619. Similar to MG-132, PR-619 caused an increase in the abundance of ubiquitinated proteins within 24 h at the concentration range of 7-12.5μM. Tested with OLN-t40 cells, PR-619, unlike MG-132, did not inhibit the enzymatic activity of the proteasome in cellular lysates but only when taken up by living cells[2]. An in vitro system showed that PR-619 was able to stabilize the microtubule network and led to small tau aggregates surrounding the microtubule organizing center [5].
There is still not any available result regarding in vivo treatment in an animal body.
References:
[1]. Mikael Altun, Holger B. Kramer, Lianne I. Willems, et al. Activity-Based Chemical Proteomics Accelerates Inhibitor Development for Deubiquitylating Enzymes. Chemistry & Biology, 2011, 18(11): 1401-1412.
[2]. Veronika Seiberlicha, Olaf Goldbauma, Victoria Zhukareva, et al. The small molecule inhibitor PR-619 of deubiquitinating enzymes affects the microtubule network and causes protein aggregate formation in neural cells: Implications for neurodegenerative diseases. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2012, 1823(11): 2057–2068.
[3]. Iraia García-Santisteban, Godefridus J Peters, Elisa Giovannetti, et al. USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy. Molecular Cancer, 2013, 12:91.
[4]. Maria Stella Ritorto, Richard Ewan, Ana B. Perez-Oliva, et al. Screening of DUB activity and specificity by MALDI-TOF mass spectrometry. Nature Communications, 2014, 5:4763.
[5]. Laura J Blair, Bo Zhang and Chad A Dickey, et al. Potential synergy between tau aggregation inhibitors and tau chaperone modulators. Alzheimer's Research & Therapy, 2013, 5:41.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt223.28
Cas No.2645-32-1
FormulaC7H5N5S2
Solubility≥11.15mg/mL in DMSO, <2.65 mg/mL in EtOH, <2.5 mg/mL in H2O
Chemical Name(2,6-diamino-5-thiocyanatopyridin-3-yl) thiocyanate
SDFDownload SDF
Canonical SMILESC1=C(C(=NC(=C1SC#N)N)N)SC#N
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

细胞实验: [1]

细胞系

OLN-t40细胞,GFP-LC3-OLN细胞

制备方法

该化合物在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

间接免疫荧光测定:18小时。

实验结果

使用编码GFP-LC3融合蛋白的质粒稳定转染OLN-t40细胞,10 μM PR-619给药18小时,使用针对LC3的抗体进行间接免疫荧光。9 μM PR-619 处理GFP-LC3-OLN细胞16小时,随后,将细胞在37℃下与LysoTracker Red(250 nM)孵育30分钟。结果表明,PR-619代表了具有广泛特异性的DUB抑制剂。此外,PR-619不会损害自噬流量。

References:

[1] Veronika Seiberlich, Janika Borchert, VIctora Zhukareva, Christiane Richter-Landsberg. Inhibition of Protein Debiquitination by PR-619 Activates the Autophagic Pathway in OLN-t40 Oligodendroglial Cells. Cell Biochem Biophys , 2013; 67:149–160.

生物活性

描述 PR-619是一种非选择性的、可逆的去泛素化酶(DUBs)抑制剂,EC50值为1-20 μM。
靶点 USP2 core USP4 USP20 JOSD2 DEN1  
IC50 7.2 μM (EC50) 3.93 μM (EC50) 5.10 μM (EC50) 1.17 μM (EC50) 4.98 μM (EC50)  

质量控制

化学结构

PR-619

相关生物数据

PR-619

相关生物数据

PR-619