GSK2656157 is a potent, selective, and cell-permeable ATP-competitive inhibitor of PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase) with an IC₅₀ value of 0.9nM[1]. PERK is a key mediator of the unfolded protein response (UPR) and plays a central role in endoplasmic reticulum stress signaling[2]. GSK2656157 is commonly used in studies investigating antitumor activity, pancreatic tissue homeostasis, endoplasmic reticulum stress, and related areas[3,4].
In vitro, pretreatment of BxPC3 cells with GSK2656157 (10-30nM) for 1h followed by co-treatment with tunicamycin (5μg/mL) or thapsigargin (1μM) for 6h effectively inhibited PERK activation induced by these agents and decreased the production of downstream substrates, including phospho-eIF2α, ATF4, and CHOP. Pretreatment with GSK2656157 (1μM) for 1h prior to tunicamycin (5μg/mL) exposure for 1h blocked the impact on de novo protein synthesis upon UPR induction[2]. Additionally, pre-incubation of J774.1 cells with GSK2656157 (2.5, 5, 10μM) for 0.5h followed by stimulation with 1000ng/mL lipopolysaccharide (LPS) for 24h resulted in a dose-dependent inhibition of Caspase-1 activity and reduced LPS-induced IL-1β production[5].
In vivo, oral administration of GSK2656157 (50mg/kg/day) to CD-1 mice resulted in complete inhibition of phospho-PERK Thr980 in the pancreas within 8h[2]. In mice bearing various human tumor xenografts (BxPC3, NCI-H929, HPAC, and Capan2), oral treatment with GSK2656157 (50 or 150mg/kg; twice daily) induced dose-dependent inhibition of tumor growth in all four models. At the dose of 150mg/kg twice daily, tumor growth inhibition rates reached 54-114%[2].
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-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R-like endoplasmic reticulum kinase (PERK)[J]. Journal of Medicinal Chemistry, 2012, 55(16): 7193-7207.
[2] ATKINS C, LIU Q, MINTHORN E, et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity[J]. Cancer Research, 2013, 73(6): 1993-2002.
[3] ZHANG W, FENG D, LI Y, et al. PERK EIF2AK3 control of pancreatic β cell differentiation and proliferation is required for postnatal glucose homeostasis[J]. Cell Metabolism, 2006, 4(6): 491-497.
[4] GUPTA S, MCGRATH B, CAVENER D R. PERK regulates the proliferation and development of insulin-secreting beta-cell tumors in the endocrine pancreas of mice[J]. PLoS One, 2009, 4(11): e8008.
[5] FARZANEH Z, KALANTAR K, IRAJI A, et al. Inhibition of LPS-induced inflammatory responses by Satureja hortensis extracts in J774.1 macrophages[J]. Journal of Immunoassay and Immunochemistry, 2018, 39(3): 274-291.
GSK2656157是一种具有高效选择性的可渗透细胞的ATP竞争性PERK（PKR样内质网激酶）抑制剂，IC₅₀值为0.9nM[1]。PERK是未折叠蛋白反应（UPR）的关键介质之一，在内质网应激反应中起核心作用[2]。GSK2656157通常用于抗肿瘤活性、胰腺组织稳态及内质网应激等研究[3,4]。
在体外，GSK2656157（10-30nM）预处理BxPC3细胞1h，加入tunicamycin（5μg/mL）或thapsigargin（1μM）后继续处理6h，有效地抑制了由tunicamycin或thapsigargin诱导的PERK活化并减少了下游底物磷酸化-elF2α、ATF4和CHOP的生成。GSK2656157（1μM）预处理BxPC3细胞1h，加入tunicamycin（5μg/mL）后继续处理1h，经UPR诱导后可阻断对蛋白质从头合成的影响[2]。GSK2656157（2.5，5，10μM）与J774.1细胞预孵育0.5h，并与1000ng/mL脂多糖（LPS）孵育24h，剂量依赖性地抑制了Caspase1的活性以减少LPS诱导的1L-1β的产生[5]。
在体内，GSK2656157（50mg/kg/day）通过口服治疗CD-1小鼠，8h后小鼠胰腺中的磷酸化PERK Thr980被完全抑制[2]。GSK2656157（50或150mg/kg；每日2次）口服治疗携带各种人类肿瘤异种移植瘤（BxPC3、NCI-H929、HPAC和Capan2）的小鼠，四种肿瘤模型的生长均受到剂量依赖性抑制，在150mg/kg每日2次剂量下，肿瘤生长抑制率可达54~114%[2]。