MK-3903
目录号 : GC31361
An AMPK activator
Cas No.:1219737-12-8
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | The enzymatic reaction is performed. Briefly, the AMPK complex of interest is appropriately diluted in AMPK reaction buffer and incubated at room temperature for 30 min to yield pAMPK. Then, MK-3903 (compound 42) and pAMPK are pre-incubated by adding appropriately diluted MK-3903 in DMSO (1.2 μL total) to the reaction buffer containing pAMPK (15 μL per well), the plate is vortexed briefly and then incubated at room temperature for 30 min. The plate is sealed and incubated at room temperature for 60 min, at which time the reaction is stopped by the addition of quench buffer. EC50s and %activation parameters are calculated from %product vs. activator concentration plots[1]. |
Animal experiment: | DIO mice at 17 weeks of age are used in this study. Mice are conditioned to dosing with vehicle (5% Tween 80, 0.25% methylcellulose, 0.02% SDS) at 5 mL/kg BID for 5 days. At that time, mice are bled, glucose and insulin measured and the animals sorted into treatment groups based on glucose, insulin and body weight. Each group of animals receives administration of MK-3903 (compound 42) in vehicle at 3 mg/kg, 10 mg/kg, 30 mg/kg, or vehicle alone for 12-day BID. Another group of mice receiving MK-3903 with vehicle at 30 mg/kg for 12-day QD is included as well. Food intake and body weight are measured daily[1]. |
References: [1]. Lan P, Romero FA, et al. Hit-to-Lead Optimization and Discovery of 5-((5-([1,1'-Biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated Protein Kinase. J Med Chem. 2017 Nov 9;60(21):9040-9052. | |
MK-3903 is an activator of AMP-activated protein kinase (AMPK; EC50 = 9 nM).1 It is selective for AMPK over a kinase panel at 10 ?M, as well as the cytochrome P450 (CYP) isoforms CYP3A4 and CYP2D6 (IC50s = >50 ?M for both) and the pregnane X receptor (PXR; EC50 = >30 ?M). MK-3903 (30 mg/kg) increases muscle and liver levels of phosphorylated ACC, an AMPK substrate, and reduces insulin resistance in diet-induced obese (DIO) mice. It inhibits hepatic fatty acid synthesis in db/db mice when administered at doses ranging from 3 to 30 mg/kg.
1.Lan, P., Romero, F.A., Wodka, D., et al.Hit-to-lead optimization and discovery of 5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid (MK-3903): A novel class of benzimidazole-based activators of AMP-activated protein kinaseJ. Med. Chem.60(21)9040-9052(2017)
| Cas No. | 1219737-12-8 | SDF | |
| Canonical SMILES | ClC1=CC2=C(NC(OC3=CC=C(C)C(C(O)=O)=C3)=N2)C=C1C(C=C4)=CC=C4C5=CC=CC=C5 | ||
| 分子式 | C27H19ClN2O3 | 分子量 | 454.9 |
| 溶解度 | DMSO : 75 mg/mL (164.87 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 | 2.1983 mL | 10.9914 mL | 21.9829 mL |
| 5 mM | 0.4397 mL | 2.1983 mL | 4.3966 mL |
| 10 mM | 0.2198 mL | 1.0991 mL | 2.1983 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。
Daidzein alleviates cisplatin-induced muscle atrophy by regulating Glut4/AMPK/FoxO pathway
Cisplatin (DDP) is widely used in cancer treatment, but DDP can cause skeletal muscle atrophy and cachexia. This study explored the effect and mechanism of daidzein (DAI) in reducing DDP-induced skeletal muscle atrophy and cachexia in vivo and in vitro. DAI alleviated the weight, food intake, muscle, adipose tissue, kidney weight and forelimb grip of LLC tumour-bearing mice after DDP treatment, and did not affect the antitumour effect of DDP. DAI can reduce the decrease of the cross-sectional area of skeletal muscle fibre-induced by DDP and prevent the change of fibre type proportion. In skeletal muscle, it can inhibit Glut4/AMPK/FoxO pathway, down-regulate the expression of atrogin1 and MuRF1, and inhibit skeletal muscle protein degradation. In DDP treated C2C12 myotubes, DAI could inhibit Glut4/AMPK/FoxO pathway to reduce myotubes atrophy, while AMPK agonist MK-3903 could reverse the protective effect of DAI. These results suggest that DAI can alleviate DDP-induced skeletal muscle atrophy by downregulating the expression of Atrogin1 and MuRF1 through the regulation of Glut4/AMPK/FoxO pathway.
Hit-to-Lead Optimization and Discovery of 5-((5-([1,1'-Biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated Protein Kinase
AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid and carbohydrate metabolism resulting from insulin resistance leads to hyperglycemia, the hallmark of type 2 diabetes mellitus (T2DM). While pharmacological activation of AMPK is anticipated to improve these parameters, the discovery of selective, direct activators has proven challenging. We now describe a hit-to-lead effort resulting in the discovery of a potent and selective class of benzimidazole-based direct AMPK activators, exemplified by 5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid, 42 (MK-3903). Compound 42 exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metabolism and insulin sensitization in mice.
Trim14 promotes autophagy and chemotherapy resistance of gastric cancer cells by regulating AMPK/mTOR pathway
Objective: To study the relationship between TRIM14 expression and chemotherapy resistance of gastric cancer (GC) cells.
Methods: The expression of TRIM14 in 5-fluorouracil (5-FU)- and oxaliplation (L-OHP)-resistant GC tissues and cells were determined by qRT-PCR and western blotting. PcDNA3.1-TRIM14 and shRNA-TRIM14 vector were transfected to 5-FU-resistant GC cells (SGC7901/5-FU), and the proliferation and apoptosis of cells were measured. Animal experiments on 5-FU-resistant GC mice were performed to study the effect of TRIM14 expression on tumor size and weight, GC cell migration, and proliferation. pcDNA3.1-MK-3903 plasmid was transfected to SGC7901/5-FU cells with TRIM14 silence. The cell proliferation and apoptosis were determined. The protein expressions of Trim14, LC3, and BECLIN1 were measured by western blotting.
Results: TRIM14 was significantly upregulated in 5-FU- and L-OHP-resistant GC tissues and cells. The overexpression of TRIM14 promoted the proliferation and autophagy of SGC7901/5-FU cells, and inhibited the apoptosis. Moreover, in vivo experiment verified that the silence of TRIM14 reduced the tumor size and weight, and inhibited the migration and proliferation of GC cells in 5-FU-resistant GC mice. The overexpression of MK-3903 reversed the inhibiting role of TRIM14 knockout on the proliferation and autophagy of SGC7901/5-FU cells.
Conclusion: TRIM14 promoted chemotherapy resistance of GC cells by regulating AMPK/mTOR pathway, and may be a new biomarker for treating GC.