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 (Kd=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 stress associated 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.
GSK2606414是一种具有口服活性的选择性蛋白激酶R样内质网激酶（PERK）抑制剂，IC50值为0.4nM[1]。GSK2606414是有效的KIT抑制剂（Kd =664±294 nM），KIT是一种III型受体酪氨酸激酶（RTK）[2]。GSK2606414还可以抑制RIPK1，这是一种参与TNFα介导的细胞死亡的激酶[3]。GSK2606414具有抗癌活性，还可作为ABCG2蛋白（也称为乳腺癌耐药蛋白（BCRP））的潜在抑制剂[4]。
在体外，GSK2606414（0.01-50µM）处理人视网膜色素上皮细胞系（ARPE-19细胞）24-72h，以剂量和时间依赖性方式抑制了细胞活力，但不会诱导细胞凋亡，抑制了毒胡萝卜素（TG）诱导的eIF2α磷酸化，下调了结合蛋白同源蛋白（CHOP）和血管内皮生长因子（VEGF）的表达水平[5]。GSK2606414（0.5和1µM）处理Neuro2a细胞24h，显著降低了高葡萄糖（HG）诱导的ROS产生，减弱了HG诱导的线粒体功能障碍和神经元凋亡，降低了内质网中GRP78蛋白的表达[6]。
在体内，GSK2606414（100mg/kg/day）通过口服治疗帕金森病（PD）模型小鼠21天，保护黑质多巴胺能神经元免受神经毒素的侵害，提高了黑质致密部（SNpc）的多巴胺能神经元的存活率，改善了PD小鼠的运动表现，但会诱导胰腺毒性[7]。