PERK (Protein kinase R (PKR)-like endoplasmic reticulum kinase) is a type I endoplasmic reticulum transmembrane protein. Generally, PERK contains a stress-sensing domain facing the endoplasmic reticulum lumen and a cytosolic kinase domain. Interestingly, PERK is a major component of the unfolded protein response (UPR), which promotes the adaptation of cells to various forms of stress. Moreover, PERK responses to a variety of endoplasmic reticulum stresses implicated in numerous disease states.
Besides, PERK phosphorylates α subunit of the translation initiation factor eIF2 at serine 51. Subsequently, PERK-eIF2α phosphorylation pathway maintains insulin biosynthesis and glucose homeostasis, facilitates tumor formation and decreases the efficacy of tumor treatment with chemotherapeutic drugs.
Here, we focus on the PERK inhibitor, GSK2606414.
GSK2606414 is an orally available, potent, and selective first-in-class PERK inhibitor. Notably, GSK2606414 is a cell-permeable PERK inhibitor with an IC50 of 0.4 nM. In vivo, Pharmacological targeting of PERK by the oral administration of GSK2606414 demonstrates efficient inhibition of the pathway in the SNpc after experimental endoplasmic reticulum stress stimulation. Thus, GSK2606414 protects nigral-dopaminergic neurons against a Parkinson’s disease-inducing neurotoxin, improving motor performance. It is worth noting that, GSK2606414 treated animals develop secondary effects possibly related to pancreatic toxicity. In a word, that suggests that strategies to attenuate endoplasmic reticulum stress levels may be effective to reduce neurodegeneration in Parkinson’s disease. Specifically, GSK2606414 (50 and 150 mg/kg) also by the oral administration inhibits the growth of a human tumor xenograft in mice.
Taken together, GSK2606414 is an orally available PERK inhibitor. GSK2606414 is a potent compound of cancer and neurological diseases.
References:
[1]. Mercado G, et al. Neurobiol Dis. 2018 Apr; 112:136-148.