MK-4074
目录号 : GC31344
MK-4074是乙酰辅酶A羧化酶(acetyl-CoAcarboxylase)的肝特异性抑制剂，IC50值约为3nM。
Cas No.:1039758-22-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | Recombinant ACC protein is purified from FM3A or Sf9 cells expressing recombinant ACC by chelating chromatography or from liver by Softlink avidin resin chromatography. Purified ACC protein is incubated with MK-4074 in assay buffer containing 5 mM ATP, 250 mM acetyl-CoA, 4.1 mM NaHCO3, 0.086 mM NaH14CO3, 20 mM potassium citrate, 20 mM MgCl2, 2 mM DTT, 0.5 mg/mL BSA and 50 mM HEPES-Na (pH 7.5) for 40 min at 37°C[1]. |
Cell experiment: | For cellular assays of DNL and FAO, cells are pre-incubated with MK-4074 for 1 hr. Then the cells are incubated for additional 1-3 hr with either 65-260 mM 14C-labeled acetate or 0.018 mM 3H-labeled palmitate for DNL or FAO assay, respectively. After incubation, intracellular 14C-labeled lipids and released 3H-labeled fatty acids are extracted and measured for DNL and FAO, respectively[1]. |
Animal experiment: | Mice[1]Studies are performed in male KKAy mice or C57BL/6J mice. KKAy mice are fed a chow diet while C57BL/6J mice are fed a high-fat diet (45% fat) for 3 weeks prior to study. Mice are treated for 7 days with vehicle (distilled water, 0.2 mL/mouse) before MK-4074 administration to acclimate mice to oral dosing. Animals are drug naive at the time of study. Mice are housed individually. Male KKAy mice (n=10-11/group) are administered a single oral dose of MK-4074 (0.3 to 3 mg/kg) prior to liver slice studies. Male KKAy mice (n=5/group) are administered a single oral dose of MK-4074 (3 to 30 mg/kg) prior to measurement of liver DNL rates. Male KKAy mice (n=8/group) are administered a single oral dose of MK-4074 (10 to 100 mg/kg) and plasma ketone bodies are measured at the indicated times. Male C57BL/6J mice (n=5, veh; n=10, MK-4074) are fed chow or a high-fat/high-sucrose (HF/HS) diet for 7 weeks and vehicle or MK-4074 is administered orally (10 or 30 mg/kg/day) for 4 weeks prior to study[1]. |
References: [1]. Kim CW, et al. Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation. Cell Metab. 2017 Aug 1;26(2):394-406.e6. | |
MK-4074 is a liver-specific inhibitor of acetyl-CoA carboxylase ACC1 and ACC2 with IC50 values of approximately 3 nM.
MK-4074 strongly inhibits both ACC1 and ACC2 with IC50 values of approximately 3 nM. MK-4074 is highly liver specific because it is a substrate of organic anion transport protein (OATP) transporters that are present only in hepatocytes, and excretion of MK-4074 from hepatocytes into bile is dependent on the MRP2 efflux transporter[1].
In male KKAy mice, a mouse model of obesity, type 2 diabetes, and fatty liver, a single oral dose of MK-4074 (0.3-3 mg/kg) significantly decreases DNL in a dose-dependent manner with an ID50 value of 0.9 mg/kg 1 hr post-administration. In a time course study, MK-4074 orally at 30 mg/kg reduces hepatic DNL by 83%, 70%, and 51% at 4, 8, and 12 hr post-dose, respectively. Single oral doses of MK-4074 at 30 and 100 mg/kg significantly increases plasma total ketones, a surrogate biomarker for hepatic FAO, by 1.5-fold to 3-fold for up to 8 hr[1].
[1]. Kim CW, et al. Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation. Cell Metab. 2017 Aug 1;26(2):394-406.e6.
| Cas No. | 1039758-22-9 | SDF | |
| Canonical SMILES | O=C1CC2(CCN(C(C3=CC(OC)=C4C(N(C5CC5)C=C4C)=C3)=O)CC2)OC6=CC=C(C7=CN=CC(C(O)=O)=C7)C=C16 | ||
| 分子式 | C33H31N3O6 | 分子量 | 565.62 |
| 溶解度 | DMSO : 83.3 mg/mL (147.27 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 | 1.768 mL | 8.8399 mL | 17.6797 mL |
| 5 mM | 0.3536 mL | 1.768 mL | 3.5359 mL |
| 10 mM | 0.1768 mL | 0.884 mL | 1.768 mL |
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| 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 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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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，
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2.
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Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation
Inhibiting lipogenesis prevents hepatic steatosis in rodents with insulin resistance. To determine if reducing lipogenesis functions similarly in humans, we developed MK-4074, a liver-specific inhibitor of acetyl-CoA carboxylase (ACC1) and (ACC2), enzymes that produce malonyl-CoA for fatty acid synthesis. MK-4074 administered to subjects with hepatic steatosis for 1 month lowered lipogenesis, increased ketones, and reduced liver triglycerides by 36%. Unexpectedly, MK-4074 increased plasma triglycerides by 200%. To further investigate, mice that lack ACC1 and ACC2 in hepatocytes (ACC dLKO) were generated. Deletion of ACCs decreased polyunsaturated fatty acid (PUFA) concentrations in liver due to reduced malonyl-CoA, which is required for elongation of essential fatty acids. PUFA deficiency induced SREBP-1c, which increased GPAT1 expression and VLDL secretion. PUFA supplementation or siRNA-mediated knockdown of GPAT1 normalized plasma triglycerides. Thus, inhibiting lipogenesis in humans reduced hepatic steatosis, but inhibiting ACC resulted in hypertriglyceridemia due to activation of SREBP-1c and increased VLDL secretion.
Mechanism and therapeutic strategy of hepatic TM6SF2-deficient non-alcoholic fatty liver diseases via in vivo and in vitro experiments
Background: The lack of effective pharmacotherapies for nonalcoholic fatty liver disease (NAFLD) is mainly attributed to insufficient research on its pathogenesis. The pathogenesis of TM6SF2-efficient NAFLD remains unclear, resulting in a lack of therapeutic strategies for TM6SF2-deficient patients.
Aim: To investigate the role of TM6SF2 in fatty acid metabolism in the context of fatty liver and propose possible therapeutic strategies for NAFLD caused by TM6SF2 deficiency.
Methods: Liver samples collected from both NAFLD mouse models and human participants (80 cases) were used to evaluate the expression of TM6SF2 by using western blotting, immunohistochemistry, and quantitative polymerase chain reaction. RNA-seq data retrieved from the Gene Expression Omnibus database were used to confirm the over-expression of TM6SF2. Knockdown and overexpression of TM6SF2 were performed to clarify the mechanistic basis of hepatic lipid accumulation in NAFLD. MK-4074 administration was used as a therapeutic intervention to evaluate its effect on NAFLD caused by TM6SF2 deficiency.
Results: Hepatic TM6SF2 levels were elevated in patients with NAFLD and NAFLD mouse models. TM6SF2 overexpression can reduce hepatic lipid accumulation, suggesting a protective role for TM6SF2 in a high-fat diet (HFD). Downregulation of TM6SF2, simulating the TM6SF2 E167K mutation condition, increases intracellular lipid deposition due to dysregulated fatty acid metabolism and is characterized by enhanced fatty acid uptake and synthesis, accompanied by impaired fatty acid oxidation. Owing to the potential effect of TM6SF2 deficiency on lipid metabolism, the application of an acetyl-CoA carboxylase inhibitor (MK-4074) could reverse the NAFLD phenotypes caused by TM6SF2 deficiency.
Conclusion: TM6SF2 plays a protective role in the HFD condition; its deficiency enhanced hepatic lipid accumulation through dysregulated fatty acid metabolism, and MK-4074 treatment could alleviate the NAFLD phenotypes caused by TM6SF2 deficiency.
Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis
Fibrosis, or the accumulation of extracellular matrix, is a common feature of many chronic diseases. To interrogate core molecular pathways underlying fibrosis, we cross-examine human primary cells from various tissues treated with TGF-β, as well as kidney and liver fibrosis models. Transcriptome analyses reveal that genes involved in fatty acid oxidation are significantly perturbed. Furthermore, mitochondrial dysfunction and acylcarnitine accumulation are found in fibrotic tissues. Substantial downregulation of the PGC1α gene is evident in both in vitro and in vivo fibrosis models, suggesting a common node of metabolic signature for tissue fibrosis. In order to identify suppressors of fibrosis, we carry out a compound library phenotypic screen and identify AMPK and PPAR as highly enriched targets. We further show that pharmacological treatment of MK-8722 (AMPK activator) and MK-4074 (ACC inhibitor) reduce fibrosis in vivo. Altogether, our work demonstrate that metabolic defect is integral to TGF-β signaling and fibrosis.