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Purity: ≥98%
MK-4074 is a novel, potent and liver-specific inhibitor of acetyl-CoA carboxylase ACC1 and ACC2 which are enzymes that produce malonyl-CoA for fatty acid synthesis, with IC50 values of 3 nM. 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.
| ln Vitro |
MK-4074 has an IC50 value of about 3 nM and substantially inhibits ACC1 and ACC2. Because MK-4074 is a substrate of the organic transporter protein (OATP) transporter, which is exclusive to hepatocytes, it is heavily attached to Manhattan. However, the MRP2 efflux transporter is necessary for the excretion of MK-4074 from hepatocytes into bile [1].
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| ln Vivo |
MK-4074 was administered as a single dosage in KKAy mice, a mouse model of transplantation, 2-diabetes, and fatty liver disease. The dose-dependent reduction of DNL was seen with an ID50 of one hour post-dose, and a value of 0.9 mg/kg. 30 mg/kg of MK-4074 decreased epidermal DNL by 83%, 70%, and 51% at 4, 8, and 12 hours after the experiment, respectively, in a prior time course investigation. For a maximum of eight hours, single doses of MK-4074 at 30 and 100 mg/kg markedly raised antibiotic total ketones, a surrogate biomarker for FAO, by 1.5 to 3 times [1].
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| 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
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| Molecular Formula |
C33H31N3O6
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| Molecular Weight |
565.615748643875
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| CAS # |
1039758-22-9
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| Related CAS # |
1039758-22-9 (free acid);1039758-18-3 (sodium);
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| 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
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| Synonyms |
MK4074; MK 4074; MK-4074
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~88.40 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.42 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.42 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7680 mL | 8.8399 mL | 17.6797 mL | |
| 5 mM | 0.3536 mL | 1.7680 mL | 3.5359 mL | |
| 10 mM | 0.1768 mL | 0.8840 mL | 1.7680 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Liver Targeting ACC1 and ACC2 Inhibitor MK-4074.Cell Metab.2017 Aug 1;26(2):394-406.e6. |
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Phase 1 Clinical Pharmacology.Cell Metab.2017 Aug 1;26(2):394-406.e6. |
MK-4074 Decreased Hepatic TGs but Increased Plasma TGs in Humans.
SREBP-1c Levels are Increased in ACC dLKO Mouse Livers.Cell Metab.2017 Aug 1;26(2):394-406.e6. |
Liver TGs are Reduced in ACC dLKO Mice, but Plasma TGs are Elevated in ACC dLKO Mice.Cell Metab.2017 Aug 1;26(2):394-406.e6. |
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Dietary PUFA Supplementation Normalizes SREBP-1c in ACC dLKO Mouse Livers. |
 Liver TG Secretion from Livers of ACC dLKO Mice is Increased and Knockdown of GPAT1 Expression Normalizes Plasma TGs.Cell Metab.2017 Aug 1;26(2):394-406.e6. |
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