MK-28 is a potent and selective agonist of pancreatic endoplasmic reticulum kinase (PERK), which functions by modulating the endoplasmic reticulum stress response[1]. MK-28 exhibits favorable pharmacokinetic properties and has the ability to cross the blood-brain barrier[2]. MK-28 has been shown to improve motor and executive function, as well as effectively extend the survival period, in a Huntington's disease mouse model[3].
In vitro, pretreatment of STHdhQ111/111 striatal cells (a Huntington's disease model) with MK-28 (5-100μM) for 48 hours significantly reduced endoplasmic reticulum stress-induced apoptosis, while concurrently increasing the levels of eIF2α phosphorylation and ATF4 protein expression[2].
In vivo, administration of MK-28 (0.3-1mg/kg) via intraperitoneal injection three times per week, starting from 3 weeks of age in R6/2 Huntington's disease model mice, significantly ameliorated motor dysfunction and extended their survival[3].
References:
[1] Costa MFD, Höglinger GU, Rösler TW. Development of a cell-free screening assay for the identification of direct PERK activators. PLoS One. 2023 May 18;18(5):e0283943.
[2] Ganz J, Shacham T, Kramer M, et al. A novel specific PERK activator reduces toxicity and extends survival in Huntington's disease models. Sci Rep. 2020 Apr 23;10(1):6875.
[3] Shacham T, Offen D, Lederkremer GZ. Efficacy of therapy by MK-28 PERK activation in the Huntington's disease R6/2 mouse model. Neurotherapeutics. 2024 Mar;21(2):e00335.
MK-28是一种有效且选择性的胰腺内质网激酶（PERK）激动剂，通过调节内质网应激反应发挥作用[1]。MK-28具备良好的药代动力学特性，并能透过血脑屏障[2]。MK-28能够改善亨廷顿病模型小鼠的运动与执行功能，并有效延长其生存期[3]。
在体外，MK-28（5-100μM）预处理STHdhQ111/111亨廷顿病模型纹状体细胞48小时，显著降低内质网应激诱导的细胞凋亡，同时增加eIF2α磷酸化水平和ATF4蛋白表达[2]。
在体内，MK-28（0.3-1mg/kg）通过每周三次腹腔注射处理3周龄开始的R6/2亨廷顿病模型小鼠，显著改善运动功能障碍并延长生存期[3]。