ZM39923
目录号 : GC37971
A potent inhibitor of JAK3
Cas No.:273727-89-2
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
Cell experiment: | PCI-37B (a metastatic SCCHN cell line expressing CCR7) cells are cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum, penicillin, and streptomycin in an atmosphere of 5% CO2 and 95% air at 37°C. The ZM39923 inhibitor treatment at the dose determined using the Cell Counting Kit-8[3]. |
References: [1]. Brown GR, et al. Naphthyl ketones: a new class of Janus kinase 3 inhibitors. Bioorg Med Chem Lett. 2000 Mar 20;10(6):575-9. | |
ZM 39923 is an inhibitor of JAK3 (IC50 = 79 nM) that less potently inhibits epidermal growth factor receptor, JAK1, and cyclin-dependent kinase 4 (IC50s = 2.4, 40, and 10 ?M, respectively).1 In the absence of the reducing agent dithiothreitol, ZM 39923 also inhibits human tissue transglutaminase 2 (TGM2) and the transglutaminase Factor XIIIa (IC50s= 10 and 25 nM, respectively).2 It breaks down in neutral buffer to form ZM 449829, which is also an inhibitor of JAK3, TGM2, and Factor XIIIa.1,2
1.Brown, G.R., Bamford, A.M., Bowyer, J., et al.Naphthyl ketones: A new class of Janus kinase 3 inhibitorsBioorg. Med. Chem. Lett.10(6)575-579(2000) 2.Lai, T.-S., Liu, Y., Tucker, T., et al.Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug librariesChem. Biol.15(9)969-978(2008)
| Cas No. | 273727-89-2 | SDF | |
| Canonical SMILES | O=C(C1=CC=C2C=CC=CC2=C1)CCN(C(C)C)CC3=CC=CC=C3 | ||
| 分子式 | C23H25NO | 分子量 | 331.45 |
| 溶解度 | Soluble 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 | 3.017 mL | 15.0852 mL | 30.1705 mL |
| 5 mM | 0.6034 mL | 3.017 mL | 6.0341 mL |
| 10 mM | 0.3017 mL | 1.5085 mL | 3.017 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。
Cytosolic TGM2 promotes malignant progression in gastric cancer by suppressing the TRIM21-mediated ubiquitination/degradation of STAT1 in a GTP binding-dependent modality
Cancer Commun (Lond) 2023 Jan;43(1):123-149.PMID:36353796DOI:10.1002/cac2.12386.
Background: Previous studies have revealed the critical role of transglutaminase 2 (TGM2) as a potential therapeutic target in cancers, but the oncogenic roles and underlying mechanisms of TGM2 in gastric cancer (GC) are not fully understood. In this study, we examined the role and potential mechanism of TGM2 in GC. Methods: Western blotting, immunohistochemistry, CCK8, colony formation and transwell assays were used to measure TGM2 expression in the GC cells and tissues and to examine the in vitro role of TGM2 in GC. Xenograft and in vivo metastasis experiments were performed to examine the in vivo role of TGM2 in GC. Gene set enrichment analysis, quantitative PCR and western blotting were conducted to screen for potential TGM2 targets involved in GC. Gain/loss-of-function and rescue experiments were conducted to detect the biological roles of STAT1 in GC cells in the context of TGM2. Co-immunoprecipitation, mass spectrometry, quantitative PCR and western blotting were conducted to identify STAT1-interacting proteins and elucidate their regulatory mechanisms. Mutations in TGM2 and two molecules (ZM39923 and A23187) were used to identify the enzymatic activity of TGM2 involved in the malignant progression of GC and elucidate the underlying mechanism. Results: In this study, we demonstrated elevated TGM2 expression in the GC tissues, which closely related to pathological grade, and predicted poor survival in patients with GC. TGM2 overexpression or knockdown promoted (and inhibited) cell proliferation, migration, and invasion, which were reversed by STAT1 knockdown or overexpression. Further studies showed that TGM2 promoted GC progression by inhibiting STAT1 ubiquitination/degradation. Then, tripartite motif-containing protein 21 (TRIM21) was identified as a ubiquitin E3 ligase of STAT1 in GC. TGM2 maintained STAT1 stability by facilitating the dissociation of TRIM21 and STAT1 with GTP-binding enzymatic activity. A23187 abolished the role of TGM2 in STAT1 and reversed the pro-tumor role of TGM2 in vitro and in vivo. Conclusions: This study revealed a critical role and regulatory mechanism of TGM2 on STAT1 in GC and highlighted the potential of TGM2 as a therapeutic target, which elucidates the development of medicine or strategies by regulating the GTP-binding activity of TGM2 in GC.
NBHA reduces acrolein-induced changes in ARPE-19 cells: possible involvement of TGFβ
Curr Eye Res 2011 Apr;36(4):370-8.PMID:21309688DOI:10.3109/02713683.2010.549601.
Purpose: Acrolein, a toxic, reactive aldehyde formed metabolically and environmentally, has been implicated in the damage to and dysfunction of the retinal pigment epithelium (RPE) that accompanies age-related macular degeneration (AMD). Our purpose was to investigate the potential of acrolein to influence the release of transforming growth factor beta-2 (TGFβ2) and vascular endothelial growth factor (VEGF), to assess the ability of N-benzylhydroxylamine (NBHA) to prevent the effect of acrolein on cytokine release and reduction of viable cells, and to explore the pathway by which acrolein might be causing the increase of VEGF. Materials and methods: Confluent ARPE-19 cells were treated with acrolein and/or NBHA. They were also pretreated with SIS3, a specific inhibitor of SMAD 3, and ZM39923, a JAK3 inhibitor, before being treated with acrolein. Viable cells were counted; ELISA was used to measure the TGFβ2 and/or VEGF in the conditioned media. Results: Acrolein was shown to reduce the number of viable ARPE-19 cells and to upregulate the release of the proangiogenic cytokines TGFβ2 and VEGF. Co-treatment with 200 μM NBHA significantly reduced the effects of acrolein on viable cell number and TGFβ2 release. Pretreatment of the cells with SIS3 partially blocked the action of acrolein on decreased viable cell number and VEGF upregulation, suggesting that part of the effects of acrolein are mediated by the increased levels of TGFβ and its signaling. Conclusions: Our results suggest that the action of acrolein on the reduction of viability and VEGF increase by ARPE-19 cells is partially mediated by TGFβ2. By reducing the effects of acrolein, NBHA and SIS3 could be potential pharmacological agents in the prevention and progression of acrolein-induced damage to the RPE that relates to AMD.
Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug libraries
Chem Biol 2008 Sep 22;15(9):969-78.PMID:18804034DOI:10.1016/j.chembiol.2008.07.015.
Human tissue transglutaminase (TGM2) is a calcium-dependent crosslinking enzyme involved in the posttranslational modification of intra- and extracellular proteins and implicated in several neurodegenerative diseases. To find specific inhibitors to TGM2, two structurally diverse chemical libraries (LOPAC and Prestwick) were screened. We found that ZM39923, a Janus kinase inhibitor, and its metabolite ZM449829 were the most potent inhibitors with IC(50) of 10 and 5 nM, respectively. In addition, two other inhibitors, including tyrphostin 47 and vitamin K(3), were found to have an IC(50) in the micromolar range. These agents used in part a thiol-dependent mechanism to inhibit TGM2, consistent with the activation of TGM2 by reduction of an intramolecular disulfide bond. These inhibitors were tested in a polyglutamine-expressing Drosophila model of neurodegeneration and found to improve survival. The TGM2 inhibitors we discovered may serve as valuable lead compounds for the development of orally active TGM2 inhibitors to treat human diseases.
Jak3 is involved in CCR7-dependent migration and invasion in metastatic squamous cell carcinoma of the head and neck
Oncol Lett 2017 May;13(5):3191-3197.PMID:28521425DOI:10.3892/ol.2017.5861.
Patients with cervical lymph node metastasis in squamous cell carcinoma of the head and neck (SCCHN) exhibit a poor prognosis and low 5-year survival rate. It has been proven that chemokine receptor 7 (CCR7) promotes cellular migration and invasion in metastatic SCCHN. In the present study, the metastatic SCCHN PCI-37B cell line was utilized to explore the role of Janus activated kinase-3 (Jak3) in the CCR7-mediated signaling pathway in metastatic SCCHN cells. It was observed that phospho-Jak3 was expressed in SCCHN tissues. In addition, when the PCI-37B cells were analyzed in response to chemokine ligand 19 (CCL19), the ligand of CCR7, at the indicated time points, the results of the present study demonstrated that CCR7 induced Jak3 activation, and inhibition of Jak3 activity using a specific inhibitor, ZM39923, significantly attenuated CCR7-induced Jak3 phosphorylation. Migration and invasion assays and immunofluorescence staining experiments demonstrated that CCL19 promoted cell migration, invasion and F-actin rearrangment in CCR7-expressing SCCHN cells partially due to the activation of the Jak3 signaling pathway. These results demonstrate that the Jak3 signaling pathway is important for the CCR7-induced malignant biological behavior of SCCHN cells.
The molecular mechanism of curcumol on inducing cell growth arrest and apoptosis in Jurkat cells, a model of CD4⁺ T cells
Int Immunopharmacol 2014 Aug;21(2):375-82.PMID:24877754DOI:10.1016/j.intimp.2014.05.021.
CD4(+) T cells in rheumatoid arthritis (RA) express growth signaling pathway in association with deregulated growth and resistance to apoptosis. The janus kinase (Jak) 3 and signal transducer and activator of transcription (STAT) pathway play a critical role in interleukin-2 (IL-2)-induced CD4(+) T cell proliferation. The present study aimed to explore the anti-cell proliferation mechanism of curcumol, a pure monomer extracted from Chinese medical plant Rhizoma curcumae. Cell proliferation was determined using WST-1 assay after curcumol treatment. The cell cycle distribution and Bcl-2 protein expression were assessed by flow cytometry. The cellular morphology of apoptosis was evaluated by Hoechst 33258 staining. The expressions of phosphorylated-Jak3 (p-Jak3), p-STAT3, and p-STAT5a following IL-2 stimulation were determined by western blot analysis. The Electrophoretic Mobility Shift Assay was used to detect the DNA binding activities of transcription factors STAT3 and STAT5. The study results showed that curcumol could inhibit the IL-2-induced Jurkat cell proliferation in a concentration- and time-dependent manner in vitro. Curcumol could cause cell cycle arrest at the S phase, induce cell apoptosis, and inhibit the expression of Bcl-2 in a dose-dependent manner. Curcumol at 50μg/mL and Jak3 inhibitor ZM39923 could inhibit the phosphorylation of Jak3 and STAT5a. In conclusion, the underlying mechanism of curcumol on suppressing CD4(+) T cell proliferation and inducing apoptosis might partly be mediated by inhibition of Jak3-STAT5-related molecular activities and Bcl-2 expression, respectively; further studies are required in vivo to test the use of curcumol as a promising therapeutic option for RA.