GSK2606414

GSK2606414 is an orally active, selective protein kinase R-like endoplasmic reticulum kinase (PERK) inhibitor with an IC₅₀ value of 0.4 nM^[1]. GSK2606414 is a potent inhibitor of KIT (K_d=664±294 nM), a type III receptor tyrosine kinase (RTK)^[2]. GSK2606414 also inhibits RIPK1, a kinase involved in TNFα-mediated cell death^[3]. GSK2606414 has anticancer activity and is also a potential inhibitor of ABCG2 protein, also known as breast cancer resistance protein (BCRP)^[4].

In vitro, GSK2606414 (0.01-50µM) treatment of human retinal pigment epithelial cell line (ARPE-19 cells) for 24-72h inhibited cell viability in a dose- and time-dependent manner, but did not induce apoptosis, inhibited thapsigargin (TG)-induced eIF2α phosphorylation, and downregulated the expression levels of co-binding protein homologous protein (CHOP) and vascular endothelial growth factor (VEGF)^[5]. GSK2606414 (0.5 and 1µM) treatment of Neuro2a cells for 24h significantly reduced high glucose (HG)-induced ROS production, attenuated HG-induced mitochondrial dysfunction and neuronal apoptosis, and reduced the expression of GRP78 protein in the endoplasmic reticulum^[6].

In vivo, oral administration of GSK2606414 (100mg/kg/day) to Parkinson's disease (PD) model mice for 21 days protected substantia nigra dopaminergic neurons from neurotoxins, increased the survival rate of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and improved the motor performance of PD mice, but induced pancreatic toxicity^[7].

References:
[1] Axten J M, Medina J R, Feng Y, et al. Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl) phenyl] acetyl}-2, 3-dihydro-1 H-indol-5-yl)-7 H-pyrrolo [2, 3-d] pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)[J]. Journal of medicinal chemistry, 2012, 55(16): 7193-7207.
[2] Mahameed M, Wilhelm T, Darawshi O, et al. The unfolded protein response modulators GSK2606414 and KIRA6 are potent KIT inhibitors[J]. Cell death & disease, 2019, 10(4): 300.
[3] Ouyang Y. The Involvement of Receptor Interacting Protein Kinase 1 (RIPK1) in the Pathogenesis of Acute Pancreatitis[M]. The University of Liverpool (United Kingdom), 2017.
[4] Yu Z Z, Xu B Q, Wang Y Y, et al. GSK2606414 sensitizes ABCG2-overexpressing multidrug-resistant colorectal cancer cells to chemotherapeutic drugs[J]. Biomedicines, 2023, 11(11): 3103.
[5] Jiang X, Wei Y, Zhang T, et al. Effects of GSK2606414 on cell proliferation and endoplasmic reticulum stressassociated gene expression in retinal pigment epithelial cells[J]. Molecular Medicine Reports, 2017, 15(5): 3105-3110.
[6] Gundu C, Arruri V K, Sherkhane B, et al. GSK2606414 attenuates PERK/p-eIF2α/ATF4/CHOP axis and augments mitochondrial function to mitigate high glucose induced neurotoxicity in N2A cells[J]. Current research in pharmacology and drug discovery, 2022, 3: 100087.
[7] Mercado G, Castillo V, Soto P, et al. Targeting PERK signaling with the small molecule GSK2606414 prevents neurodegeneration in a model of Parkinson's disease[J]. Neurobiology of disease, 2018, 112: 136-148.