ISRIB (trans-isomer) is a small molecule compound that selectively inhibits the Integrated Stress Response (ISR) pathway. ISRIB (trans-isomer) is a highly selective inhibitor of PERK with an IC50 of 5nM[1]. Compared to the cis-isomer, the trans-isomer has higher potency and specificity. By targeting the kinase domain of Protein Kinase R (PKR)-like Endoplasmic Reticulum Kinase (PERK), ISRIB (trans-isomer)blocks the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), thereby restoring global protein synthesis while maintaining selective translation of stress response mRNAs[2]. The ISR pathway is a conserved signaling network activated by various cellular stresses, including endoplasmic reticulum stress, amino acid deprivation, and viral infection[3]. Due to ISRIB (trans-isomer) ability to modulate cellular stress responses, ISRIB (trans-isomer) is commonly used in research on neurodegenerative diseases, metabolic disorders, and inflammatory diseases[4].
In vitro, when ISRIB (trans-isomer) (500nM) is combined with Bafilomycin A1 (20nM) and added to a culture of 20000 lin⁻CB cells for 8 days, the combination of ISRIB (trans-isomer) and Bafilomycin A1 significantly reduces cell proliferation[5]. Treatment of HEK293 cells transfected with TauRD(P301S)-YFP with ISRIB (trans-isomer) (5μM) significantly increases the amount of Tau protein and promotes Tau protein aggregation[6].
In vivo, intraperitoneal injection of ISRIB (trans-isomer) (0.25mg/kg) in 8- to 10-week-old male C57BL/6J mice shortens the escape latency of mice in the Morris water maze test when searching for the hidden platform, enhancing their spatial learning ability[7]. In PS19 mice aged 8-9 months, daily intraperitoneal injection of ISRIB (trans-isomer) (5mg/kg) for 9 weeks significantly increases Tau phosphorylation in the dentate gyrus region[8].
References:
[1] Kalinin A, Zubkova E, Menshikov M. Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence. Int J Mol Sci. 2023 Dec 13;24(24):17423.
[2] Jin S, Cojocari D, Purkal JJ, et al. 5-Azacitidine Induces NOXA to Prime AML Cells for Venetoclax-Mediated Apoptosis. Clin Cancer Res. 2020 Jul 1;26(13):3371-3383.
[3] ZENG X, CHEN X, QIN H, et al. Preventive effects of a natural anti-inflammatory agent Salvianolic acid A on acute kidney injury in mice [J]. Food Chem Toxicol, 2020, 135(110901.
[4] Wang J, Hu B, Zhao Z, et al. Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver. Cell Death Dis. 2020 Jan 6;11(1):17.
[5] Xie SZ, Garcia-Prat L, Voisin V, et al. Sphingolipid Modulation Activates Proteostasis Programs to Govern Human Hematopoietic Stem Cell Self-Renewal. Cell Stem Cell. 2019 Nov 7;25(5):639-653.e7.
[6] Park G, Xu K, Chea L, et al. Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation. J Biol Chem. 2023 Feb;299(2):102821.
[7] Sidrauski C, Acosta-Alvear D, Khoutorsky A, et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife. 2013 May 28;2:e00498.
[8] Briggs DI, Defensor E, Memar Ardestani P, et al. Role of Endoplasmic Reticulum Stress in Learning and Memory Impairment and Alzheimer's Disease-Like Neuropathology in the PS19 and APPSwe Mouse Models of Tauopathy and Amyloidosis. eNeuro. 2017 Jul 14;4(4):ENEURO.0025-17.2017.
ISRIB (trans-isomer)是一种选择性抑制整合应激反应（ISR）通路的小分子化合物。ISRIB (trans-isomer)是PERK的一种高度选择性抑制剂，IC50为5nM[1]。与顺式异构体相比，反式异构体具有更高的效力和特异性，通过靶向蛋白激酶R（PKR）样内质网激酶（PERK）的激酶结构域，ISRIB (trans-isomer)阻断真核翻译起始因子2α（eIF2α）的磷酸化，从而在维持应激反应 mRNA 选择性翻译的同时恢复全局蛋白质合成[2]。ISR通路是由内质网应激、氨基酸缺乏和病毒感染等多种细胞应激激活的保守信号网络[3]，因ISRIB (trans-isomer)调节细胞应激反应的能力，常被应用于神经退行性疾病、代谢性疾病及炎症性疾病的研究[4]。
在体外，将ISRIB (trans-isomer)（500nM）与巴弗洛霉素A1（20nM）联合，添加到含有20000个lin⁻CB 细胞中培养8天，当ISRIB（trans-isomer）与巴弗洛霉素A1联合会显著降低细胞增殖[5]。ISRIB (trans-isomer)（5μM）处理转染TauRD(P301S)-YFP质粒的HEK293细胞，显著增加了Tau蛋白质数量，促进了Tau蛋白聚集[6]。
在体内，ISRIB（trans-isomer）（0.25mg/kg）腹腔注射于8-10周龄雄性C57BL/6J小鼠，缩短了小鼠在Morris水迷宫实验中寻找隐藏平台时逃逸潜伏期，增强小鼠的空间学习能力[7]。8-9月龄PS19小鼠每日腹腔注射ISRIB（trans-isomer）（5mg/kg），持续9周，ISRIB（trans-isomer）显著增加齿状回区域的Tau磷酸化增加[8]。