Ceapin-A7
(Synonyms: N-(1-(2,4-双(三氟甲基)苄基)-1H-吡唑-4-基)-5-(呋喃-2-基)异恶唑-3-甲酰胺) 目录号 : GC61606
An ATF6α inhibitor
Cas No.:2323027-38-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Ceapin-A7 is an inhibitor of activating transcription factor 6α (ATF6α; IC50 = 0.59 ?M in a reporter assay).1 It is selective for ATF6α over ATF6β at 18.9 ?M. Ceapin-A7 (6 ?M) sensitizes U2OS osteosarcoma cells to the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor and ER stress inducer thapsigargin . Chondrocyte-conditioned media from primary human chondrocytes pre-incubated with ceapin-A7 (0.5 ?M) prior to stimulation with TNF-α, IFN-γ, or IL-17 has a reduced ability to induce tube formation in human umbilical vein endothelial cells (HUVECs).2 Ceapin-A7 (15 ?M) inhibits viral RNA production in Vero cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).3
1.Gallagher, C.M., Garri, C., Cain, E.L., et al.Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branchElife5e11878(2016) 2.Ma, M., Li, H., Wang, P., et al.ATF6 aggravates angiogenesis-osteogenesis coupling during ankylosing spondylitis by mediating FGF2 expression in chondrocytesiScience24(7)102791(2021) 3.Echavarría-Consuegra, L., Cook, G.M., Busnadiego, I., et al.Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infectionPLoS Pathog.17(6)e1009644(2021)
| Cas No. | 2323027-38-7 | SDF | |
| 别名 | N-(1-(2,4-双(三氟甲基)苄基)-1H-吡唑-4-基)-5-(呋喃-2-基)异恶唑-3-甲酰胺 | ||
| Canonical SMILES | O=C(NC1=CN(CC2=CC=C(C(F)(F)F)C=C2C(F)(F)F)N=C1)C3=NOC(C4=CC=CO4)=C3 | ||
| 分子式 | C20H12F6N4O3 | 分子量 | 470.32 |
| 溶解度 | DMSO: 100 mg/mL (212.62 mM) | 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 | 2.1262 mL | 10.6311 mL | 21.2621 mL |
| 5 mM | 0.4252 mL | 2.1262 mL | 4.2524 mL |
| 10 mM | 0.2126 mL | 1.0631 mL | 2.1262 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
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，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
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。
Activating transcription factor 6 protects against endothelial barrier dysfunction
Cell Signal 2022 Nov;99:110432.PMID:35933031DOI:10.1016/j.cellsig.2022.110432.
Background: Endothelial hyperpermeability is associated with sepsis and acute respiratory distress syndrome (ARDS). The identification of molecular pathways involved in barrier dysfunction; may reveal promising therapeutic targets to combat ARDS. Unfolded protein response (UPR) is a highly conserved molecular pathway, which ameliorates endoplasmic reticulum stress. The present work focuses on the effects of ATF6, which is a UPR sensor, in lipopolysaccharides (LPS)-induced endothelial hyperpermeability. Methods: The in vitro effects of AA147 and Ceapin-A7 in LPS-induced endothelial barrier dysfunction were investigated in bovine pulmonary artery endothelial cells (BPAEC). Small interfering (si) RNA was utilized to "silence" ATF6, and electric cell-substrate impedance sensing (ECIS) measured transendothelial resistance. Fluorescein isothiocyanate (FITC)-dextran assay was utilized to assess paracellular permeability. Protein expression levels were evaluated with Western blotting, and cell viability with MTT assay. Results: We demonstrated that AA147 prevents LPS-induced barrier disruption by counteracting Cofilin and myosin light chain 2 (MLC2) activation, as well as VE-Cadherin phosphorylation. Moreover, this ATF6 inducer opposed LPS-triggered decrease in transendothelial resistance (TEER), as well as LPS-induced paracellular hyperpermeability. On the other hand, ATF6 suppression due to Ceapin-A7 or small interfering RNA exerted the opposite effects, and potentiated LPS-induced endothelial barrier disruption. Moderate concentrations of both ATF6 modulators did not affect cell viability. Conclusions: ATF6 activation protects against endothelial barrier function, suggesting that this UPR sensor may serve as a therapeutic target for sepsis and ARDS.
ATF6α contributes to rheumatoid arthritis by inducing inflammatory cytokine production and apoptosis resistance
Front Immunol 2022 Oct 10;13:965708.PMID:36300114DOI:10.3389/fimmu.2022.965708.
Objective: The contribution of activating transcription factor 6α (ATF6α) in rheumatoid arthritis (RA) pathogenesis, especially on fibroblast-like synoviocytes (FLSs), has been suggested by its sensitivity to inflammatory stimulus. However, the exact role and therapeutic potential of ATF6α in RA remains to be fully elucidated. Methods: ATF6α expression was determined in joint tissues and FLS, and gain-of-function and loss-of-function analyses were applied to evaluate the biological roles of ATF6α in RA FLSs. A murine collagen-induced arthritis (CIA) model, combining both gene deletion of ATF6α and treatment with the ATF6α inhibitor Ceapin-A7, was employed. Joint inflammation, tissue destruction, circulating levels of inflammatory cytokines were assessed in CIA mice. Transcriptome sequencing analysis (RNASeq), molecular biology, and biochemical approaches were performed to identify target genes of ATF6α. Results: ATF6α expression was significantly increased in synovium of RA patients and in synovium of mice subjected to CIA. ATF6α silencing or inhibition repressed RA FLSs viability and cytokine production but induced the apoptosis. CIA-model mice with ATF6α deficiency displayed decreased arthritic progression, leading to profound reductions in clinical and proinflammatory markers in the joints. Pharmacological treatment of mice with Ceapin-A7 reduced arthritis severity in CIA models. RNA-sequencing of wild-type and knockdown of ATF6α in RA FLSs revealed a transcriptional program that promotes inflammation and suppresses apoptosis, and subsequent experiments identified Baculoviral IAP Repeat Containing 3 (BIRC3) as the direct target for ATF6α. Conclusion: This study highlights the pathogenic role of ATF6α-BIRC3 axis in RA and identifies a novel pathway for new therapies against RA.
The functional implication of ATF6α in castration-resistant prostate cancer cells
FASEB J 2023 Feb;37(2):e22758.PMID:36607288DOI:10.1096/fj.202201347R.
Stress in the endoplasmic reticulum (ER) may perturb proteostasis and activates the unfolded protein response (UPR). UPR activation is frequently observed in cancer cells and is believed to fuel cancer progression. Here, we report that one of the three UPR sensors, ATF6α, was associated with prostate cancer (PCa) development, while both genetic and pharmacological inhibition of ATF6α impaired the survival of castration-resistance PCa (CRPC) cells. Transcriptomic analyses identified the molecular pathways deregulated upon ATF6α depletion, and also discovered considerable disparity in global gene expression between ATF6α knockdown and Ceapin-A7 treatment. In addition, combined analyses of human CRPC bulk RNA-seq and single-cell RNA-seq (scRNA-seq) public datasets confirmed that CRPC tumors with higher ATF6α activity displayed higher androgen receptor (AR) activity, proliferative and neuroendocrine (NE) like phenotypes, as well as immunosuppressive features. Lastly, we identified a 14-gene set as ATF6α NE gene signature with encouraging prognostic power. In conclusion, our results indicate that ATF6α is correlated with PCa progression and is functionally relevant to CRPC cell survival. Both specificity and efficacy of ATF6α inhibitors require further refinement and evaluation.
ATF6 aggravates angiogenesis-osteogenesis coupling during ankylosing spondylitis by mediating FGF2 expression in chondrocytes
iScience 2021 Jun 28;24(7):102791.PMID:34296071DOI:10.1016/j.isci.2021.102791.
Although angiogenesis-osteogenesis coupling is important in ankylosing spondylitis (AS), therapeutic agents targeting the vasculature remain elusive. Here, we identified activating transcription factor 6 (ATF6) as an important regulator of angiogenesis in the pathogenesis of AS. First, we found that ATF6 and fibroblast growth factor 2 (FGF2) levels were higher in SKG mice and in cartilage of pateints with AS1. The proangiogenic activity of human chondrocytes was enhanced by the activation of the ATF6-FGF2 axis following 7 days of stimulation with inflammatory factors, e.g., tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ) or interleukin-17 (IL-17). Mechanistically, ATF6 interacted with the FGF2 promotor and promoted its transcription. Treatment with the ATF6 inhibitor Ceapin-A7 inhibited angiogenesis in vitro and angiogenesis-osteogenesis coupling in vivo. ATF6 may aggravate angiogenesis-osteogenesis coupling during AS by mediating FGF2 transcription in chondrocytes, implying that ATF6 represents a promising therapeutic target for AS.
Zika Virus Induces an Atypical Tripartite Unfolded Protein Response with Sustained Sensor and Transient Effector Activation and a Blunted BiP Response
mSphere 2021 Jun 30;6(3):e0036121.PMID:34106769DOI:10.1128/mSphere.00361-21.
To study how the Zika virus (ZIKV) interacts with the host unfolded protein response (UPR), we undertook a kinetics study. We show that ZIKV infection triggers an atypical tripartite UPR in A549 cells involving transient activation of the effectors X-box-binding protein 1, activating transcription factor 4 (ATF4), CCAAT enhancer-binding protein-homologous protein, and growth arrest and DNA damage-inducible protein 34 during early infection and sustained activation of all three UPR sensors: RNA-activated protein kinase-like endoplasmic reticulum-resident kinase (PERK), inositol-requiring kinase-1α (IRE1α), and ATF6. Sustained phosphorylation of the eukaryotic translation initiation factor 2α and rRNA degradation coincide with host translational shutoff, cell lysis, and virus release during late infection. We show a blunted response of the master negative regulator, the immunoglobulin heavy-chain-binding protein (BiP), by chemical UPR inducers, and we show that ZIKV suppresses BiP transcription and translation, suggesting that it may be necessary to blunt the BiP response to sustain UPR sensor activation. The PERK inhibitor GSK2606414 alone has no effects but synergizes with the ATF6 inhibitor Ceapin-A7 to inhibit early and late infection, whereas Ceapin-A7 alone inhibits late infection. Likewise, 4-phenylbutyric acid inhibits ZIKV replication by attenuating the PERK and ATF6 pathways and potentiating the IRE1α pathway, suggesting that ZIKV infection is differentially and temporally regulated by different UPR arms. ZIKV infection is inhibited by pretreatment of chemical UPR inducers but is refractory to the inhibitory activity of chemical inducers once infection has been established, suggesting that ZIKV has anti-UPR mechanisms that may be able to modulate and co-opt the UPR in its life cycle. IMPORTANCE The Zika virus originates from Africa and Asia but is emerging in other parts of the world. It usually causes an asymptomatic or mild, acute infection but can cause serious neurological complications, such as microcephaly and Guillain-Barré syndromes. Therefore, there is a pressing need for an antiviral. Viruses are obligative parasites and are dependent on the hosts for their propagation. As a result, we can target viruses by targeting host dependency. The host unfolded protein response is a cellular homeostatic response to stresses but can also be triggered by virus infections. We show here that Zika virus infection can cause stress and trigger the unfolded protein response. The Zika virus is able to manipulate, subvert, and co-opt the host unfolded protein response to aid its own replication. Understanding host dependency is important in the quest of a new class of antivirals called host-targeting agents.