VX-745
(Synonyms: VX-745) 目录号 : GC12926
A p38α MAPK inhibitor
Cas No.:209410-46-8
Sample solution is provided at 25 µL, 10mM.
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VX-745 is a first-generation inhibitor of p38αMAPK with IC50 value of 1.0 μM when tested with Werner syndrome dermal fibroblasts [1].
Mammalian mitogen-activated protein (MAP) kinases are serine /threonine kinases and have 4 subfamilies: ERK, JNK, MAPKp38 and ERK5. MAPK pathway plays a pivotal role in transmitting signals from cell membrane to nucleus and also participates in many intracellular signaling pathways that control a wide spectrum of cellular processes (growth, differentiation, stress responses, cancer progression) [2]. MAPKp38 is originally isolated from lipopolysaccharide-stimulated monocytes. And according to the distribution in tissue, regulation of kinase activation and subsequent phosphorylation of downstream substrates, it is divided into four isoforms p38alpha, p38beta, p38gamma and p38delta [3].
VX-745 is an exquisite kinase selectively inhibit p38αMAPK and is regarded as an anti-inflammatory candidate. When tested with PBMCs or whole blood, VX-745 treatment could inhibit the secretion of IL-1β and TNF-α in vitro [4]. In human dermal fibroblast cells, VX-745 treatment blocked p38 signaling to rescue the aging phenotype in Werner syndrome [5].
References:
[1]. Bagley, M.C., et al., Microwave-assisted Ullmann C-S bond formation: synthesis of the P38alpha MAPK clinical candidate VX-745. J Org Chem, 2009. 74(21): p. 8336-42.
[2]. Dent, P., et al., MAPK pathways in radiation responses. Oncogene, 2003. 22(37): p. 5885-96.
[3]. Dominguez, C., D.A. Powers, and N. Tamayo, p38 MAP kinase inhibitors: many are made, but few are chosen. Curr Opin Drug Discov Devel, 2005. 8(4): p. 421-30.
[4]. Duffy, J.P., et al., The Discovery of VX-745: A Novel and Selective p38alpha Kinase Inhibitor. ACS Med Chem Lett, 2011. 2(10): p. 758-63.
[5]. Bagley, M.C., et al., Gram-scale synthesis of the p38alpha MAPK-inhibitor VX-745 for preclinical studies into Werner syndrome. Future Med Chem, 2010. 2(9): p. 1417-27.
| Kinase experiment [1]: | |
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Spectrophotometric coupled-enzyme assay |
A fixed concentration of enzyme (15 nM of p38α or p38β) was incubated with VX-745 in DMSO for 10 mins at 30 °C in 0.1 M HEPES buffer, pH 7.5, containing 10% glycerol, 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg/mL pyruvate kinase, 50 μg/mL lactate dehydrogenase and 200 μM EGF receptor peptide (KRELVEPLTPSGEAPNQALLR). The reaction was initiated with 100 μM and 70 μM ATP for p38α and p38β assays, respectively. The decrease of absorbance at 340 nm was monitored to follow the rate of the reaction. IC50 was evaluated from the rate data as a function of the inhibitor concentration. |
| Cell experiment [2]: | |
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Cell lines |
Human bone marrow stromal cells (BMSCs) and multiple myeloma (MM) cells |
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Preparation method |
The solubility of this compound in DMSO is > 21.8 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months. |
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Reacting condition |
60 nM ~ 20 μM; 48 hrs |
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Applications |
In BMSCs, VX-745 inhibited IL-6 and VEGF secretion, without affecting their viability. VX-745 also reduced TNF-α-induced IL-6 secretion in BMSCs. In addition, VX-745 inhibited both MM cell proliferation and IL-6 secretion in BMSCs induced by adherence of MM cells to BMSCs, which implied that VX-745 could inhibit paracrine MM cell growth in the bone marrow milieu, as well as overcome cell adhesion-related drug resistance. |
| Animal experiment [1]: | |
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Animal models |
A type II collagen-induced arthritis (CIA) mice model |
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Dosage form |
2.5, 5 and 10 mg/kg; p.o.; b.i.d., for 20 days |
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Applications |
In a CIA mice model, VX-745 at the doses of 2.5, 5, and 10 mg/kg improved the inflammatory scores by 27%, 31% and 44%, respectively. In addition, compared with the vehicle control group, VX-745 also improved the histological scores by 32 ~ 39%, which indicated its protection on bone and cartilage erosion. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Duffy, J.P., et al., The Discovery of VX-745: A Novel and Selective p38alpha Kinase Inhibitor. ACS Med Chem Lett, 2011. 2(10): p. 758-63. [2]. Hideshima T, Akiyama M, Hayashi T, Richardson P, Schlossman R, Chauhan D, Anderson KC. Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu. Blood. 2003 Jan 15;101(2):703-5. |
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| Cas No. | 209410-46-8 | SDF | |
| 别名 | VX-745 | ||
| 化学名 | 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenyl)sulfanylpyrimido[1,6-b]pyridazin-6-one | ||
| Canonical SMILES | C1=CC(=C(C(=C1)Cl)C2=C3C=CC(=NN3C=NC2=O)SC4=C(C=C(C=C4)F)F)Cl | ||
| 分子式 | C19H9Cl2F2N3OS | 分子量 | 436.27 |
| 溶解度 | ≥ 21.8mg/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 | 2.2922 mL | 11.4608 mL | 22.9216 mL |
| 5 mM | 0.4584 mL | 2.2922 mL | 4.5843 mL |
| 10 mM | 0.2292 mL | 1.1461 mL | 2.2922 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。
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet