MK8722 is an orally allosteric pan-AMPK activator that supports glucose homeostasis, with EC50 values of 1-60nM[1]. MK8722 binds to the allosteric drug and metabolite (ADaM) site between the α-kinase domain and the β-glycogen-binding domain, stabilizes the enzyme’s activation loop in an active conformation, and allows bypassing the need for AMPKα T172 phosphorylation for full enzyme activation [2]. MK8722 has been widely used in animal models to regulate blood glucose levels and glucose uptake[3].
In vitro, MK8722 treatment for 48h significantly inhibited the proliferation of A2780, OV90, and SKOV3 cells with IC50 values of 35.47, 36.44 and 47.89μg/ml, respectively[4]. Treatment of PANC-1 cells with 50μM MK8722 for 24h significantly reduced colony formation and inhibited cell invasion and migration[5]. Pretreatment with 10μM MK8722 for 30min reduced the abundance of Bax, Caspase-3, and the Bax/Bcl-2 ratio and increased the abundance of SIRT3 and MnSOD activity in H2O2-induced bovine mammary alveolar cells (MAC-T)[6].
In vivo, MK8722 treatment via daily subcutaneous injection at a dose of 30mg/kg for 4 weeks in 4-month-old male HSALR mice improved the alternative splicing of Atp2a1 in the tibialis anterior muscle and resulted in the activation of AMPK and a switch of oxidative metabolism[7]. Daily oral administration of MK8722 at a dose of 30mg/kg for 30 days attenuated paclitaxel-induced hyperalgesia in male and female mice[8].
References:
[1] Myers R W, Guan H P, Ehrhart J, et al. Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy[J]. Science, 2017, 357(6350): 507-511.
[2] Doshi H, Spengler K, Godbole A, et al. AMPK protects endothelial cells against HSV-1 replication via inhibition of mTORC1 and ACC1[J]. Microbiology Spectrum, 2023, 11(5): e00417-23.
[3] Feng D, Biftu T, Romero F A, et al. Discovery of MK-8722: a systemic, direct pan-activator of AMP-activated protein kinase[J]. ACS medicinal chemistry letters, 2018, 9(1): 39-44.
[4] Wang L, Zhu H, Shi Z, et al. MK8722 initiates early-stage autophagy while inhibiting late-stage autophagy via FASN-dependent reprogramming of lipid metabolism[J]. Theranostics, 2024, 14(1): 75.
[5] Wang C, Huang B, Sun L, et al. MK8722, an AMPK activator, inhibiting carcinoma proliferation, invasion and migration in human pancreatic cancer cells[J]. Biomedicine & Pharmacotherapy, 2021, 144: 112325.
[6] Liu L, Lu O, Li D, et al. Sirtuin 3 mitigates oxidative-stress-induced apoptosis in bovine mammary epithelial cells[J]. Journal of Dairy Science, 2023, 106(10): 7266-7280.
[7] Ravel‐Chapuis A, Fahmi C, Gobin J, et al. The AMPK allosteric activator MK‐8722 improves the histology and spliceopathy in myotonic dystrophy type 1 (DM1) skeletal muscle[J]. The FASEB Journal, 2024, 38(23): e70199.
[8] Inyang K E, McDougal T A, Ramirez E D, et al. Alleviation of paclitaxel-induced mechanical hypersensitivity and hyperalgesic priming with AMPK activators in male and female mice[J]. Neurobiology of Pain, 2019, 6: 100037.
MK8722是一种口服变构泛AMPK激活剂，能够调节葡萄糖稳态，EC50值在1-60nM范围内[1]。MK8722通过结合于AMPK的变构药物和代谢物位点（位于α激酶结构域和β糖原结合结构域之间），稳定酶激活环的活性构象，从而绕过AMPKα T172磷酸化以实现酶完全激活[2]。MK8722已广泛应用于动物模型中，用于调节血糖水平和葡萄糖摄取[3]。
在体外，MK8722处理48小时能显著抑制A2780、OV90和SKOV3细胞的增殖，IC50值分别为35.47、36.44和47.89μg/ml[4]。用50μM的MK8722处理PANC-1细胞24小时，可显著减少细胞克隆形成，并抑制细胞侵袭和迁移能力[5]。在过氧化氢诱导的牛乳腺肺泡细胞中，用10μM的MK8722预处理30分钟，能够降低Bax、Caspase-3的丰度及Bax/Bcl-2比值，同时提高SIRT3的丰度和MnSOD活性[6]。
在体内，对4月龄雄性HSALR小鼠每日皮下注射30mg/kg剂量的MK8722，连续4周，可改善胫骨前肌中Atp2a1基因的可变剪接，并导致AMPK 的激活和氧化代谢的转变[7]。每日以30mg/kg剂量口服MK8722，连续30天，能够减轻紫杉醇诱导的雄性和雌性小鼠痛觉过敏[8]。