Englerin A
(Synonyms: 恩格林A) 目录号 : GC64459
Englerin A 是一种有效和选择性的 TRPC4 和 TRPC5 通道的活化剂，EC50 值分别为 11.2 和 7.6 nM。Englerin A 通过增加 Ca2+ 内流和 Ca2+ 细胞超负荷来诱导肾癌细胞死亡。
Cas No.:1094250-15-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Englerin A is a potent and selective activator of TRPC4 and TRPC5 channels, with EC50s of 11.2 and 7.6 nM, respectively. Englerin A can induce renal carcinoma cells death by elevated Ca2+ influx and Ca2+ cell overload[1][2][3].
Englerin A (0.15-2500 nM; 48 h) characteristic concentration-dependent suppresses cells growth of the A-498 cells treated with the control siRNA while has little effect on the growth of cells treated with TRPC4 siRNAs[3].Englerin A (0.001nM-10 μM; 48 h) inhibits cells viability in HEK293T cells overexpressing TRPC5[3].Englerin A (3 nM; 1-240 s) evokes sustained elevation of the intracellular Ca2+ concentration within 1 min in HEK 293 cells over-expressing human TRPC4[1].Englerin A (0.1-1000 nM; 1-300 s) evokes intracellular Ca2+ elevations in A498 cells as well with an EC50 of 10 nM[1].
Englerin A (5 mg/kg; i.p daily except Sunday) markedly inhibits tumor growth during the 2-week treatment period in mice[4].
[1]. Akbulut Y, et, al. (-)-Englerin A is a potent and selective activator of TRPC4 and TRPC5 calcium channels. Angew Chem Int Ed Engl. 2015 Mar 16;54(12):3787-91.
[2]. Rubaiy HN, et, al. Identification of an (-)-englerin A analogue, which antagonizes (-)-englerin A at TRPC1/4/5 channels. Br J Pharmacol. 2018 Mar; 175(5):830-839.
[3]. Carson C, et, al. Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation. PLoS One. 2015 Jun 22;10(6):e0127498.
[4]. Sourbier C, et, al. Englerin A stimulates PKCθ to inhibit insulin signaling and to simultaneously activate HSF1: pharmacologically induced synthetic lethality. Cancer Cell. 2013 Feb 11;23(2):228-37.
| Cas No. | 1094250-15-3 | SDF | Download SDF |
| 别名 | 恩格林A | ||
| 分子式 | C26H34O6 | 分子量 | 442.54 |
| 溶解度 | 储存条件 | Store at -20°C | |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2597 mL | 11.2984 mL | 22.5968 mL |
| 5 mM | 0.4519 mL | 2.2597 mL | 4.5194 mL |
| 10 mM | 0.226 mL | 1.1298 mL | 2.2597 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Biological Effects of Modifications of the Englerin A Glycolate
ACS Med Chem Lett 2022 Aug 22;13(9):1472-1476.PMID:PMC9465829DOI:10.1021/acsmedchemlett.2c00258.
Modifications at the glycolate moiety of Englerin A were made to explore variations at the most sensitive site on the molecule for activity in the NCI 60 screen, wherein Englerin A is highly potent and selective for renal cancer cells. Replacement of the glycolate by other functionalities as well as esterification of the glycolate hydroxyl yielded compounds which displayed excellent selectivity and potency compared with the natural product. TRPC4/5 ion channel experiments with five compounds showed delayed or reduced agonism with TRPC5, at much higher concentrations than Englerin A. With TRPC4, these compounds all had no effect at 10 μM. The same compounds were not detectable in mouse serum after a single oral dose of 12.5 mg/kg. At 100 mg/kg p.o., no toxicity was observed, and blood levels were barely detectable. Intravenous administration led to toxicity but at substantially lower doses than for Englerin A.
Englerin A Rewires Phosphosignaling via Hsp27 Hyperphosphorylation to Induce Cytotoxicity in Renal Cancer Cells
J Proteome Res 2022 Aug 5;21(8):1948-1960.PMID:35838755DOI:10.1021/acs.jproteome.2c00248.
Englerin A (EA) is a small-molecule natural product with selective cytotoxicity against renal cancer cells. EA has been shown to induce apoptosis and cell death through cell-cycle arrest and/or insulin signaling pathways. However, its biological mode of action or targets in renal cancer remains enigmatic. In this study, we employed advanced mass spectrometry-based phosphoproteomics approaches to identify EA's functional roles in renal cancer. We identified 10,940 phosphorylation sites, of which 706 sites exhibited EA-dependent phosphorylation changes. Integrated analysis of motifs and interaction networks suggested activation of stress-activated kinases including p38 upon EA treatment. Of note, a downstream target of p38, Hsp27, was found to be hyperphosphorylated on multiple sites upon EA treatment. Among these, a novel site Ser65 on Hsp27, which was further validated by targeted proteomics, was shown to be crucial for EA-induced cytotoxicity in renal cancer cells. Taken together, these data reveal the complex signaling cascade that is induced upon EA treatment and importantly provide insights into its effects on downstream molecular signaling.
Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation
PLoS One 2015 Jun 22;10(6):e0127498.PMID:26098886DOI:10.1371/journal.pone.0127498.
Englerin A is a structurally unique natural product reported to selectively inhibit growth of renal cell carcinoma cell lines. A large scale phenotypic cell profiling experiment (CLiP) of Englerin A on ¬over 500 well characterized cancer cell lines showed that Englerin A inhibits growth of a subset of tumor cell lines from many lineages, not just renal cell carcinomas. Expression of the TRPC4 cation channel was the cell line feature that best correlated with sensitivity to Englerin A, suggesting the hypothesis that TRPC4 is the efficacy target for Englerin A. Genetic experiments demonstrate that TRPC4 expression is both necessary and sufficient for Englerin A induced growth inhibition. Englerin A induces calcium influx and membrane depolarization in cells expressing high levels of TRPC4 or its close ortholog TRPC5. Electrophysiology experiments confirmed that Englerin A is a TRPC4 agonist. Both the Englerin A induced current and the Englerin A induced growth inhibition can be blocked by the TRPC4/C5 inhibitor ML204. These experiments confirm that activation of TRPC4/C5 channels inhibits tumor cell line proliferation and confirms the TRPC4 target hypothesis generated by the cell line profiling. In selectivity assays Englerin A weakly inhibits TRPA1, TRPV3/V4, and TRPM8 which suggests that Englerin A may bind a common feature of TRP ion channels. In vivo experiments show that Englerin A is lethal in rodents near doses needed to activate the TRPC4 channel. This toxicity suggests that Englerin A itself is probably unsuitable for further drug development. However, since Englerin A can be synthesized in the laboratory, it may be a useful chemical starting point to identify novel modulators of other TRP family channels.
Englerin A selectively induces necrosis in human renal cancer cells
PLoS One 2012;7(10):e48032.PMID:23144724DOI:10.1371/journal.pone.0048032.
The number of renal cancers has increased over the last ten years and patient survival in advanced stages remains very poor. Therefore, new therapeutic approaches for renal cancer are essential. Englerin A is a natural product with a very potent and selective cytotoxicity against renal cancer cells. This makes it a promising drug candidate that may improve current treatment standards for patients with renal cancers in all stages. However, little is known about Englerin A's mode of action in targeting specifically renal cancer cells. Our study is the first to investigate the biological mechanism of Englerin A action in detail. We report that Englerin A is specific for renal tumor cells and does not affect normal kidney cells. We find that Englerin A treatment induces necrotic cell death in renal cancer cells but not in normal kidney cells. We further show that autophagic and pyroptotic proteins are unaffected by the compound and that necrotic signaling in these cells coincided with production of reactive oxygen species and calcium influx into the cytoplasm. As the first study to analyze the biological effects of Englerin A, our work provides an important basis for the evaluation and validation of the compound's use as an anti-tumor drug. It also provides a context in which to identify the specific target or targets of Englerin A in renal cancer cells.
Importance of a 4-Alkyl Substituent for Activity in the Englerin Series
ACS Med Chem Lett 2017 Jun 6;8(7):746-750.PMID:28740610DOI:10.1021/acsmedchemlett.7b00161.
The ring closing metathesis/transannular etherification approach to the englerin nucleus was adapted to provide two key intermediates for analogue synthesis: the 4-desmethyl Δ5,6 tricycle and the 4-oxo Δ5,6 tricycle. The former was elaborated to 4-desmethyl Englerin A and the latter served as a common precursor for Englerin A, 4-ethyl Englerin A, and 4-isopropyl Englerin A. 4-Desmethyl Englerin A was less active than the natural product by an order of magnitude, but the 4-ethyl and 4-isopropyl analogues were comparable in activity to Englerin A. These results are consistent with the premise that the 4-alkyl group enforces the binding conformation of the cinnamoyl ester substituent. Furthermore, they suggest that 4-alkyl englerin structures may prove to be useful tool compounds.