XAV-939
(Synonyms: 3,5,7,8-四氢-2-[4-(三氟甲基)苯基]-4H-噻喃并[4,3-D]嘧啶-4-酮) 目录号 : GC12781
A TNKS inhibitor
Cas No.:284028-89-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
A549 cells |
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Preparation Method |
A549 cells in the logarithmic growth phase were seeded in 96-well plates, at a density of 2×104 cells/well, and subsequently treated with various XAV-939 concentrations (0.1, 0.5, 1, 5, 10 µmol/l) for 24, 48, 72 and 96 h. |
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Reaction Conditions |
0.1, 0.5, 1, 5, 10 µmol/l for 24, 48, 72 and 96 h |
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Applications |
At all experimental time points, XAV-939 treatment was able to significantly inhibit A549 cell proliferation compared with the control group (F24h=30.382, F48h=52.463, F72h=56.635, F96h=59.274), with the exception of the 5-and 10-µmol/l groups at the 24 h time point. |
| Animal experiment [2]: | |
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Animal models |
DBA/2 inbred mice |
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Preparation Method |
Mice received an intraperitoneal injection of 100 µl of XAV-939 (2 mg/ml) along with a 10% dimethyl sulfoxide (DMSO; compounded by 0.9% NaCl solution) every day since they received vaccination with the L1210 cells, while according to other experimental groups, mice received intraperitoneal injections along with 100 µl of 10% DMSO solution (compounded by 0.9% NaCl solution) for 21 days continuously. |
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Dosage form |
Intraperitoneal injection, 100 µl of 2 mg/ml for 21 days |
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Applications |
In the model, NC, HOTAIR mimics, siRNA HOTAIR, XAV-939, and HOTAIR mimics + XAV-939 groups, the WBC number in PB increased on the 21st day by 341.08, 355.72, 499.85, 196.49, 187.48, and 363.35%. However, the PLT number decreased by 66.37, 69.46, 81.27, 49.24, 50.47, and 72.61%; hemoglobin content decreased by 39.02, 41.05, 60.52, 14.01, 17.20, and 42.36%. |
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References: [1]: Li C, Zheng X, Han Y, Lv Y, Lan F, Zhao J. XAV939 inhibits the proliferation and migration of lung adenocarcinoma A549 cells through the WNT pathway. Oncol Lett. (2018) 15:8973-82. doi: 10.3892/ol.2018.8491 |
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XAV-939 selectively inhibits β-catenin-mediated transcription. XAV-939 stimulates β-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2 with IC50 values of 5 nM and 2 nM, respectively [1，2].
XAV-939 inhibited mouse neurofibroma sphere formation with IC50 of 0.1 μM. Western blot confirmed a 50% decrease in total β-catenin with 3 days of XAV-939 exposure (10 nM) [3]. TNKS1 plays a role in cell cycle regulation and that XAV-939 induces an accumulation of NB cell lines at G2/M and S phase of the cell cycle [4].
XAV-939 increases Irradiation (IR) sensitivity of cervical cancer with the PIK3CA-E545K mutation in vivo, XAV-939 and IR inhibited tumor weight by 38% from IR alone in that with PIK3CA-WT [5]. Combinatorial inhibition of transforming growth factor-β (TGF-β) and WNT signaling with SB431542 and XAV-939 potently enhances the efficiency, quality, and speed of reprogrammed iCMs generated upon delivery of the minimal transcription factor (TF) cocktail, GMT, into postnatal cardiac fibroblasts. SB431542 and XAV-939 significantly improved in vivo reprogramming and cardiac function in mice compared with GMT alone and reduced the number of TFs needed for human reprogramming [6].
References:
[1]. S.M. Huang, Y.M. Mishina, S. Liu, A. Cheung, F. Stegmeier, G.A. Michaud, O. Charlat, E. Wiellette, Y. Zhang, S. Wiessner, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signaling.Nature, 461 (2009), pp. 614-620
[2]. Mohit Narwal, et al. Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity. J Med Chem. 2013 Oct 24;56(20):7880-9.
[3]. Wu J, Keng VW, Patmore DM, et al. Insertional mutagenesis identifies a STAT3/Arid1b/beta-catenin pathway driving neurofibroma initiation. Cell Rep. 2016;14:1979-90.
[4]. X.H. Tian, W.J. Hou, Y. Fang, J. Fan, H. Tong, S.L. Bai, et al. XAV939, a tankyrase 1 inhibitior, promotes cell apoptosis in neuroblastoma cell lines by inhibiting Wnt/β-catenin signaling pathway. J Exp Clin Cancer Res, 32 (1) (2013 Dec 5), p. 1
[5]. Jiang W, Wu Y, He T, et al. Targeting of beta-catenin reverses radioresistance of cervical cancer with the PIK3CA E545K mutation. Mol Cancer Ther 2020;19(2):337-47.
[6]. Mohamed, T. M. et al. Chemical enhancement of in vitro and in vivo direct cardiac reprogramming. Circulation 135, 978-995 (2017).
XAV-939 选择性抑制 β-连环蛋白介导的转录。 XAV-939 通过稳定轴蛋白（破坏复合物的浓度限制成分）来刺激 β-连环蛋白降解。 XAV939 通过抑制多聚 ADP 核糖基化酶 tankyrase 1 和 tankyrase 2 来稳定 axin，IC50 值分别为 5 nM 和 2 nM [1，2]。
XAV-939 抑制小鼠神经纤维瘤球体形成，IC50 为 0.1 μM。 Western blot 证实，XAV-939 暴露 (10 nM) 3 天后，总 β-连环蛋白减少了 50% [3]。 TNKS1在细胞周期调控中发挥作用，XAV-939诱导NB细胞系在细胞周期的G2/M期和S期积累[4]。
XAV-939 在体内增加了具有 PIK3CA-E545K 突变的宫颈癌的辐照 (IR) 敏感性，XAV-939 和 IR 抑制了 38% 的肿瘤重量，与 PIK3CA-WT 单独使用 IR 相比 [5] 。使用 SB431542 和 XAV-939 联合抑制转化生长因子-β (TGF-β) 和 WNT 信号转导，可有效提高将最小转录因子 (TF) 混合物 GMT 递送至细胞内后生成的重编程 iCM 的效率、质量和速度产后心脏成纤维细胞。与单独使用 GMT 相比，SB431542 和 XAV-939 显着改善了小鼠的体内重编程和心脏功能，并减少了人类重编程所需的 TF 数量[6]。
| Cas No. | 284028-89-3 | SDF | |
| 别名 | 3,5,7,8-四氢-2-[4-(三氟甲基)苯基]-4H-噻喃并[4,3-D]嘧啶-4-酮 | ||
| 化学名 | 2-[4-(trifluoromethyl)phenyl]-1,5,7,8-tetrahydrothiopyrano[4,3-d]pyrimidin-4-one | ||
| Canonical SMILES | C1CSCC2=C1NC(=NC2=O)C3=CC=C(C=C3)C(F)(F)F | ||
| 分子式 | C14H11F3N2OS | 分子量 | 312.31 |
| 溶解度 | ≥ 15.62mg/mL in DMSO | 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 | 3.2019 mL | 16.0097 mL | 32.0195 mL |
| 5 mM | 0.6404 mL | 3.2019 mL | 6.4039 mL |
| 10 mM | 0.3202 mL | 1.601 mL | 3.2019 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。
Activation of endothelial Wnt/β-catenin signaling by protective astrocytes repairs BBB damage in ischemic stroke
The role of astrocytes in dysregulation of blood-brain barrier (BBB) function following ischemic stroke is not well understood. Here, we investigate the effects of restoring the repair properties of astrocytes on the BBB after ischemic stroke. Mice deficient for NHE1, a pH-sensitive Na+/H+ exchanger 1, in astrocytes have reduced BBB permeability after ischemic stroke, increased angiogenesis and cerebral blood flow perfusion, in contrast to wild-type mice. Bulk RNA-sequencing transcriptome analysis of purified astrocytes revealed that ?177 genes were differentially upregulated in mutant astrocytes, with Wnt7a mRNA among the top genes. Using a Wnt reporter line, we confirmed that the pathway was upregulated in cerebral vessels of mutant mice after ischemic stroke. However, administration of the Wnt/β-catenin inhibitor, XAV-939, blocked the reparative effects of Nhe1-deficient astrocytes. Thus, astrocytes lacking pH-sensitive NHE1 protein are transformed from injurious to "protective" by inducing Wnt production to promote BBB repair after ischemic stroke.
Treatment with XAV-939 prevents in vitro calcification of human valvular interstitial cells
The development of a substance or inhibitor-based treatment strategy for the prevention of aortic valve stenosis is a challenge and a main focus of medical research in this area. One strategy may be to use the tankyrase inhibitor XAV-939, which leads to Axin stabilisation and subsequent destruction of the β-catenin complex and dephosphorylation of β-catenin. The dephosphorylated active form of β-catenin (non-phospho-β-catenin) then promotes nuclear transcription that leads to osteogenesis. The aims of the present study were to develop an experimental system for inducing in vitro calcification of human aortic valvular interstitial cells (VICs) to investigate the potential anti-calcific effect of XAV-939 and to analyse expression of the Wnt signalling proteins and Sox9, a chondrogenesis regulator, in this model. Calcification of human VIC cultures was induced by cultivation in an osteogenic medium and the effect of co-incubation with 1μM XAV-939 was monitored. Calcification was quantified when mineral deposits were visible in culture and was histologically verified by von Kossa or Alizarin red staining and by IR-spectroscopy. Protein expression of alkaline phosphatase, Axin, β-catenin and Sox9 were quantified by western blotting. In 58% of the VIC preparations, calcification was induced in an osteogenic culture medium and was accompanied by upregulation of alkaline phosphatase. The calcification induction was prevented by the XAV-939 co-treatment and the alkaline phosphatase upregulation was suppressed. As expected, Axin was upregulated, but the levels of active non-phospho-β-catenin were also enhanced. Sox9 was induced during XAV-939 treatment but apparently not as a result of downregulation of β-catenin signalling. XAV-939 was therefore able to prevent calcification of human VIC cultures, and XAV-939 treatment was accompanied by upregulation of active non-phospho-β-catenin. Although XAV-939 does not downregulate active β-catenin, treatment with XAV-939 results in Sox9 upregulation that may prevent the calcification process.
Inhibition of Wnt/β-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis
Osteoarthritis (OA) is a degenerative joint disease involving both cartilage and synovium. The canonical Wnt/β-catenin pathway, which is activated in OA, is emerging as an important regulator of tissue repair and fibrosis. This study seeks to examine Wnt pathway effects on synovial fibroblasts and articular chondrocytes as well as the therapeutic effects of Wnt inhibition on OA disease severity. Mice underwent destabilization of the medial meniscus surgery and were treated by intra-articular injection with XAV-939, a small-molecule inhibitor of Wnt/β-catenin signaling. Wnt/β-catenin signaling was highly activated in murine synovial fibroblasts as well as in OA-derived human synovial fibroblasts. XAV-939 ameliorated OA severity associated with reduced cartilage degeneration and synovitis in vivo. Wnt inhibition using mechanistically distinct small-molecule inhibitors, XAV-939 and C113, attenuated the proliferation and type I collagen synthesis in synovial fibroblasts in vitro but did not affect human OA-derived chondrocyte proliferation. However, Wnt modulation increased COL2A1 and PRG4 transcripts, which are downregulated in chondrocytes in OA. In conclusion, therapeutic Wnt inhibition reduced disease severity in a model of traumatic OA via promoting anticatabolic effects on chondrocytes and antifibrotic effects on synovial fibroblasts and may be a promising class of drugs for the treatment of OA.
Tankyrase inhibitor XAV-939 enhances osteoblastogenesis and mineralization of human skeletal (mesenchymal) stem cells
Tankyrase is part of poly (ADP-ribose) polymerase superfamily required for numerous cellular and molecular processes. Tankyrase inhibition negatively regulates Wnt pathway. Thus, Tankyrase inhibitors have been extensively investigated for the treatment of clinical conditions associated with activated Wnt signaling such as cancer and fibrotic diseases. Moreover, Tankyrase inhibition has been recently reported to upregulate osteogenesis through the accumulation of SH3 domain-binding protein 2, an adaptor protein required for bone metabolism. In this study, we investigated the effect of Tankyrase inhibition in osteoblast differentiation of human skeletal (mesenchymal) stem cells (hMSCs). A Tankyrase inhibitor, XAV-939, identified during a functional library screening of small molecules. Alkaline phosphatase activity and Alizarin red staining were employed as markers for osteoblastic differentiation and in vitro mineralized matrix formation, respectively. Global gene expression profiling was performed using the Agilent microarray platform. XAV-939, a Tankyrase inhibitor, enhanced osteoblast differentiation of hBMSCs as evidenced by increased ALP activity, in vitro mineralized matrix formation, and upregulation of osteoblast-related gene expression. Global gene expression profiling of XAV-939-treated cells identified 847 upregulated and 614 downregulated mRNA transcripts, compared to vehicle-treated control cells. It also points towards possible changes in multiple signaling pathways, including TGFβ, insulin signaling, focal adhesion, estrogen metabolism, oxidative stress, RANK-RANKL (receptor activator of nuclear factor κB ligand) signaling, Vitamin D synthesis, IL6, and cytokines and inflammatory responses. Further bioinformatic analysis, employing Ingenuity Pathway Analysis identified significant enrichment in XAV-939-treated cells of functional categories and networks involved in TNF, NFκB, and STAT signaling. We identified a Tankyrase inhibitor (XAV-939) as a powerful enhancer of osteoblastic differentiation of hBMSC that may be useful as a therapeutic option for treating conditions associated with low bone formation.