MK8722 |
| Catalog No.: GC31470 |
MK8722 is a potent and systemic pan-AMPK activator.
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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Purity: >99.50%
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Animal experiment: |
Mice[1]Housing Lean C57BL/6 mice at 10-12 weeks of age and C57BL/6 eDIO mice at 16 weeks of age are used. db/db mice at 7 weeks of age are used. Animals are maintained on a 12 hr/12 hr light-dark cycle with free access to food and water with the temperature maintained at 22ºC. Four lean C57BL/6 mice are housed in a standard cage. eDIO mice are individually caged. Eight db/db mice are housed in a large rodent cage. C57BL/6 mice and db/db mice are maintained on regular rodent chow diet 7012 (5% dietary fat; 3.75 kcal/g) for 1-2 weeks before receiving compound treatments. eDIO mice are maintained on 60% kcal% fat diet. Oral dosing of MK8722 in standard vehicle, or vehicle alone, is performed using 10 mL/kg body weight. The effect of MK8722 on various metabolic parameters is established by comparison to vehicle treated animals[1]. |
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References: [1]. Myers RW, et al. Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiachypertrophy. Science. 2017 Aug 4;357(6350):507-511. |
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MK8722 is a potent and systemic pan-AMPK activator.
MK8722 (MK-8722) is a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. MK8722 activates pAMPK complexes with increased potency and magnitude versus AMP, with EC50 values of ~1 to 60 nM and increased activation by factors of ~4 to 24. Although MK8722 exhibits higher affinity for β1-containing (~1 to 6 nM) versus β2-containing (~15 to 63 nM) pAMPK complexes, it is the most potent activator of β2 complexes reported to date. pAMPK activation by maximal AMP plus MK8722 is synergistic, demonstrating that the agents act at distinct sites[1].
Chronic antihyperglycemic efficacy of MK8722 (MK-8722) is evaluated in db/db mice, a leptin receptor-deficient T2DM model. Once-daily administration of MK8722 results in dose-dependent lowering of ambient blood glucose. On treatment day 12, glucose reductions after MK8722 treatment (30 mpk/day) are comparable to those observed with the PPARγ agonist rosiglitazone (3 mpk/day). Unlike Rosiglitazone, the glucose-lowering action of MK8722 manifests without significant effects on body weight, which is a consistent finding. Dose-dependent increases in tissue pACC are maintained throughout the dosing period. Chronic efficacy, without tachyphylaxis, is also observed in additional dysmetabolic and diabetic rodent models. In all cases, efficacy is associated with trough MK8722 plasma levels comparable to the concentrations required to acutely stimulate skeletal muscle glucose uptake. Chronic MK8722 dosing in mice also increases muscle Glut4 protein levels, possibly contributing to efficacy[1].
[1]. Myers RW, et al. Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiachypertrophy. Science. 2017 Aug 4;357(6350):507-511.
| Cas No. | 1394371-71-1 | SDF | |
| Canonical SMILES | O[C@H]1[C@@]([C@]2([H])OC1)([H])OC[C@H]2OC3=NC4=NC(C(C=C5)=CC=C5C6=CC=CC=C6)=C(Cl)C=C4N3 | ||
| Formula | C24H20ClN3O4 | M.Wt | 449.89 |
| Solubility | DMSO : ≥ 62.5 mg/mL (138.92 mM) | Storage | Store at -20°C |
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. | ||
| Shipping Condition | Evaluation sample solution : ship with blue ice All other available size: ship with RT , or blue ice upon request |
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MK8722, an AMPK activator, inhibiting carcinoma proliferation, invasion and migration in human pancreatic cancer cells
Background: MK8722 is a potent and systemic pan-AMPK activator. It is an effective, direct, allosteric activator of AMPK complex in many mammals. This study tried to explore the underlying anti-cancer molecular mechanism of MK8722 in human pancreatic cancer cells (PCCs). Methods: The anti-proliferation, invasion and migration functions of MK8722 in human pancreatic cancer analyzed by real time cellular analysis, colony formation assay, cell migration assay, transwell assay and flow cytometery analysis. Moreover, the potential targeted signaling pathway was tested via RNA-seq and pathway enrichment analysis. Results: In the present study, we investigated the anti-PCCs effects of MK8722 on two different human pancreatic cancer cell lines (PANC-1 and Patu8988). The results showed that MK8722 significantly inhibited human tumor cells proliferation and migration/invasion in a dose-dependent manner. Additionally, the influence of MK8722 was examined by analyzing the expression of potential key genes and pathways, which may provide novel insights to the mechanism of MK8722. Conclusion: The inhibition of pancreatic cancer by MK8722 through a number of pathways that inhibit carcinoma proliferation, invasion and migration. The potential effect of MK8722 might be determined by regulating the expression of AL162151, IER2, REPIN1, KRT80 to inhibit cycle arrest and migration.
Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722-mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.
Evaluation of AMPK activity in mice by measuring activator-induced glucose uptake
The AMP-activated protein kinase (AMPK) is a principal nutrient sensor and a master regulator of cellular energy homeostasis. Once activated, AMPK induces glucose uptake, which leads to a transient decrease in blood glucose level and can be used as an indicator of AMPK activity. Here, we present a protocol accessing AMPK activity in mice by measuring glucose uptake induced by AMPK activators, MK8722 and A769662. This protocol can be used to evaluate AMPK signaling in vivo under various pathophysiological conditions. For complete details on the use and execution of this protocol, please refer to Jiang et al. (2021).
Alleviation of paclitaxel-induced mechanical hypersensitivity and hyperalgesic priming with AMPK activators in male and female mice
AMP-activated protein kinase (AMPK) is an energy-sensing kinase that has emerged as a novel therapeutic target for pain due to its ability to inhibit mechanistic target of rapamycin (mTOR) and mitogen activated protein kinase (MAPK) signaling, two signaling pathways that are linked to pain promotion after injury as well as the development of hyperalgesic priming. MAPK and mTOR signaling are also implicated in chemotherapy induced peripheral neuropathy (CIPN). We conducted a series of experiments to gain further insight into how AMPK activators might best be used to treat pain in both sexes in the setting of CIPN from paclitaxel. We also assessed whether hyperalgesic priming emerges from paclitaxel treatment and if this can be prevented by AMPK targeting. AMPK can be pharmacologically activated indirectly through regulation of upstream kinases like liver kinase B1 (LKB1) or directly using positive allosteric modulators. We used the indirect AMPK activators metformin and narciclasine, both of which have been shown to reduce pain in preclinical models but with much different potencies and different efficacies depending on the sex of the animal. We used the direct AMPK activator MK8722 because it is the most potent and specific such activator described to date. Here, the AMPK activators were used in 2 different treatment paradigms. First the drugs were given concurrently with paclitaxel to test whether they prevent mechanical hypersensitivity. Second the AMPK activators were given after the completion of paclitaxel treatment to test whether they reverse established mechanical hypersensitivity. Consistent with our previously published findings with metformin, narciclasine (1 mg/kg) produced an anti-hyperalgesic effect, preventing paclitaxel-induced neuropathy in outbred mice of both sexes. In contrast to metformin, narciclasine also reversed mechanical hypersensitivity in established CIPN. Both metformin (200 mg/kg) and narciclasine prevented the development of hyperalgesic priming induced by paclitaxel treatment. MK8722 (30 mg/kg) had no effect on mechanical hypersensitivity caused by paclitaxel in either the prevention or reversal treatment paradigms. However, MK8722 did attenuate hyperalgesic priming in male and female mice. We conclude that paclitaxel induces robust hyperalgesic priming that is prevented by AMPK targeting and that narciclasine is a particularly attractive candidate for further development as a CIPN treatment.
Indirect AMP-Activated Protein Kinase Activators Prevent Incision-Induced Hyperalgesia and Block Hyperalgesic Priming, Whereas Positive Allosteric Modulators Block Only Priming in Mice
AMP-activated protein kinase (AMPK) is a multifunctional kinase that negatively regulates the mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signaling, two signaling pathways linked to pain promotion after injury, such as surgical incision. AMPK can be activated directly using positive allosteric modulators, as well as indirectly through the upregulation of upstream kinases, such as liver kinase B1 (LKB1), which is a mechanism of action of metformin. Metformin's antihyperalgesic effects occur only in male mice, raising questions about how metformin regulates pain sensitivity. We used metformin and other structurally distinct AMPK activators narciclasine (NCLS), ZLN-024, and MK8722, to treat incision-induced mechanical hypersensitivity and hyperalgesic priming in male and female mice. Metformin was the only AMPK activator to have sex-specific effects. We also found that indirect AMPK activators metformin and NCLS were able to reduce mechanical hypersensitivity and block hyperalgesic priming, whereas direct AMPK activators ZLN-024 and MK8722 only blocked priming. Direct and indirect AMPK activators stimulated AMPK in dorsal root ganglion (DRG) neuron cultures to a similar degree; however, incision decreased phosphorylated AMPK (p-AMPK) in DRG. Because AMPK phosphorylation is required for kinase activity, we interpret our findings as evidence that indirect AMPK activators are more effective for treating pain hypersensitivity after incision because they can drive increased p-AMPK through upstream kinases like LKB1. These findings have important implications for the development of AMPK-targeting therapeutics for pain treatment. SIGNIFICANCE STATEMENT: Nonopioid treatments for postsurgical pain are needed. Our work focused on whether direct or indirect AMP-activated protein kinase (AMPK) activators would show greater efficacy for inhibiting incisional pain, and we also tested for potential sex differences. We conclude that indirect AMPK activators are likely to be more effective as potential therapeutics for postsurgical pain because they inhibit acute pain caused by incision and prevent the long-term neuronal plasticity that is involved in persistent postsurgical pain. Our work points to the natural product narciclasine, an indirect AMPK activator, as an excellent starting point for development of therapeutics.
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