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PYR-41

现货
Catalog No.
B1492
泛素活化酶(E1)抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 650.00
现货
10mg
¥ 1,030.00
现货
25mg
¥ 1,890.00
现货

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Background

Ubiquitylation is catalyzed by the sequential action of ubiquitinactivating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a ubiquitin protein ligase (E3). Ubiquitylation is essential to numerous cellular and developmental processes, including protein quality control, growth, apoptosis, antigen presentation, DNA repair, and signal transduction. PYR-41, 4[4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester, is a selective inhibitor of Ubiquitin-Activating Enzyme (E1).

In vitro: In addition to blocking ubiquitylation, PYR-41 was found to increase total sumoylation in cells. PYR-41 could attenuate cytokine-mediated nuclear factor-KBactivation. This correlated with inhibition of nonproteasomal ubiquitylation of TRAF6, which is important to IKBkinase activation. PYR-41 also prevented the downstream ubiquitylation and proteasomal degradation of IKBA. Moreover, PYR-41 has demonstrated effective UAE E1 inhibition as well as some off-target inhibition of the other ubiquitin regulatory enzymes and signal-transducing proteins, suggesting it is a nonspecific inhibitor [1].

In vivo: No animal in vivo data have been published so far.

Clinical trial: Up to now, PYR-41 is still in the preclinical development stage.

Reference:
[1] Yang Y1 Kitagaki J, Dai RM, Tsai YC, Lorick KL, Ludwig RL, Pierre SA, Jensen JP, Davydov IV, Oberoi P, Li CC, Kenten JH, Beutler JA, Vousden KH, Weissman AM.  Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics. Cancer Res. 2007 Oct 1;67(19):9472-81.

文献引用

1. Lee MJ, Miller Z, et al. "H727 cells are inherently resistant to the proteasome inhibitor carfilzomib, yet require proteasome activity for cell survival and growth." Sci Rep. 2019 Mar 11;9(1):4089. PMID:30858500
2. Susman MW, Karuna EP, et al. "Kinesin superfamily protein Kif26b links Wnt5a-Ror signaling to the control of cell and tissue behaviors in vertebrates." Elife. 2017 Sep 8;6. pii: e26509. PMID:28885975

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt371.3
Cas No.418805-02-4
FormulaC17H13N3O7
Solubility≥18.55mg/mL in DMSO
Chemical Nameethyl 4-[(4Z)-4-[(5-nitrofuran-2-yl)methylidene]-3,5-dioxopyrazolidin-1-yl]benzoate
SDFDownload SDF
Canonical SMILESCCOC(=O)C1=CC=C(C=C1)N2C(=O)C(=CC3=CC=C(O3)[N+](=O)[O-])C(=O)N2
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, 2]:

细胞系

RPE细胞,转染GFPu的U2OS细胞; RAW 264.7细胞

溶解方法

在DMSO中的溶解度>18.6mg/mL。为了获得更高的浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。

反应条件

RPE细胞: 50 μmol/L; 30 min; 37°CRAW 264.7细胞: 5, 10和20 μM

应用

在RPE细胞中,PYR-41显著降低Ub-E1硫酯,IC50值为10-25μmol/ L。PYR-41还阻断响应于蛋白酶体抑制剂ALLN的泛素缀合物的积累。 在转染GFPu的U2OS细胞中,PYR-41抑制GFPu的泛素化和蛋白酶体降解。在LPS刺激的RAW 264.7细胞中,PYR-41(10和20μM)分别将IκB的表达水平恢复到非LPS刺激的RAW 264.7细胞中的89%和95%。PYR-41也降低TNF-α水平。

动物实验[2]:

动物模型

通过盲肠结扎穿刺(CLP)诱导败血症的雄性C57BL / 6小鼠

剂量

5 mg/kg; CLP后立即静脉注射

应用

在CLP诱导的败血症小鼠中,PYR-41分别显著降低促炎细胞因子TNF-α,IL-1β和IL-6的血清水平,分别为79%,77%和89%。PYR-41还将器官损伤标记物AST,ALT和LDH的血清水平分别降低了27%,43%和52%。用PYR-41治疗改善了肺组织的形态学表现,组织学损伤评分降低了74%。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同,这是由实验系统的误差引起的,属于正常现象。

References:

[1] Yang Y1 Kitagaki J, Dai RM, Tsai YC, Lorick KL, Ludwig RL, Pierre SA, Jensen JP, Davydov IV, Oberoi P, Li CC, Kenten JH, Beutler JA, Vousden KH, Weissman AM. Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics. Cancer Res. 2007 Oct 1;67(19):9472-81.

[2]. Matsuo S1, Sharma A, Wang P, et al. PYR-41, A Ubiquitin-Activating Enzyme E1 Inhibitor, Attenuates Lung Injury in Sepsis. Shock. 2017 Jun 28.

质量控制

化学结构

PYR-41

相关生物数据

PYR-41

相关生物数据

PYR-41