Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is an endoplasmic reticulum-associated stress sensor protein. PERK phosphorylates eukaryotic initiation factor 2α (eIF2α) to induce translation attenuation in response to ER stress. PERK is also a regulator of lipogenesis during adipocyte differentiation through activation of the cleavage of sterol regulatory element-binding protein 1 (SREBP1). MK-28 is a potent small-molecule PERK activator.
MK-28 is a PERK activator in a Huntington’s disease cellular model. Especially, MK-28 selectively activates PERK using purified components in vitro. MK-28 shows PERK selectivity in vitro on a 391-kinase panel from ER stress-induced apoptosis. Moreover, MK-28 exhibits remarkable pharmacokinetic properties and high blood-brainbarrier penetration in mice. Transient subcutaneous delivery of MK-28 significantly improves motor and executive functions and delays death onset in R6/2 mice, showing no toxicity. MK-28 is non-toxic and neuroprotective in Huntington’s disease model striatal neurons. Furthermore, MK-28 rescues cells from endoplasmic reticulum stress-induced apoptosis. MK-28 reduces apoptosis by 40% at 10 μM and is also effective at lower concentrations.
MK-28 exhibits brain penetrance and improves neurological functions in the R6/2 HD mouse model. In particular, MK-28 improves systemic function and survival in R6/2 mice and induces increased levels of eIF2α-P in the mouse brain striatum. MK-28 exhibits remarkable pharmacokinetic properties in mice. MK-28 becomes readily available and is stable in plasma, penetrates the blood-brain barrier, and is stable inside the brain following single IP injection. In addition, MK-28 exhibits a notable pharmacokinetic profile and brain bioavailability in mice.
In summary, MK-28 is a potent and selective PERK activator and exhibits a notable pharmacokinetic profile and brain bioavailability in mice.
Javier Ganz, 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.