|N,N'-(反式-环己烷-1,4-二基)双(2-(4-氯苯氧基)乙酰胺)|CsnPharm

CAS No.: 1597403-47-8

N,N'-(trans-cyclohexane-1,4-diyl)bis(2-(4-chlorophenoxy)acetamide) Catalog No. CSN17942

Synonyms: trans-ISRIB

ISRIB is a potent inhibitor of PERK signaling showing inhibition of the ATF4 luciferase reporter in HEK293T cells with IC50 of 5 nM.

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靶点选择性

生物活性

实验方案

技术信息

生物活性

靶点 PERK

IC50:5nM
描述Diverse stress signals converge at a single phosphorylation event at serine 51 of eIF2α, kinases of which are PERK, GCN2, PKR and HRI and this four kinases form a collection of signaling pathways termed the “integrated stress response” (ISR) as they converge on the same molecular event. The ternary complex (eIF2-GTP-Met-tRNAi) can associate with the 40S ribosomal subunit forming the 43S pre-initiation complex (PIC) that scans the 5' UTR of mRNAs to select the initiating AUG codon. ISRIB as a potent ISR (integrated stress response) inhibitor, which functions downstream of all eIF2α kinases. The ISRIB trans-Isomer showed effect on inhibition of the ATF4 luciferase reporter in HEK293T cells treated with 2 µg/ml of tunicamycin to induce ER stress with IC50 value of 5nM. Treatment with 200nM ISRIB trans-Isomer blocked production of endogenous ATF4 induced by tunicamycin or thapsigargin, the targets of ATF4 including CHOP and GADD34, as well as blocked ATF4 induction after activation of either GCN2 or HRI, but did not affect XBP1 mRNA splicing, XBP1s production or PERK phosphorylation in HEK293T cells, suggesting that ISRIB specifcally blocks signaling of the PERK-branch of the UPR but did not impair PERK phosphorylation or activation of the ATF6-branch of the UPR. ISRIB did not block eIF2α phosphorylation under ER stress-inducing conditions, even increased the level of eIF2α phosphorylation at 120 min after tunicamycin addition, suggesting that ISRIB may function on effects downstream of PERK and eIF2α phosphorylation, but not PERK or eIF2α phosphorylation itself. A further experiment showed that ISRIB trans-Isomer can help maintain high PIC levels even when eIF2α is phosphorylated and exert its function by maintaining elevated ternary complex (eIF2-GTP-Met-tRNAi) levels. ISRIB addition caused a strong synergistic effect on ER-stressed cells by tunicamycin, reducing colony number and size due to apoptosis signifcantly more than ER-stress alone in HEK293T cells, while ISRIB itself did not affect cell viability alone. ISRIB is brain permeable. Animal dosed with ISRIB showed enhancement on both hippocampusdependent spatial learning and hippocampus-dependent contextual fear conditioning^[1].
作用机制ISRIB trans-Isomer can exert its function by maintaining elevated ternary complex (eIF2-GTP-Met-tRNAi) levels. Notice that ER stress remains unmitigated in ISRIB-treated cells is supported by sustained activation of all three UPR sensors including PERK, IRE1 and ATF6.^[1]
动物研究
剂量
Mice^[2] (i.p.): 0.25 mg/kg - 5 mg/kg

给药途径
i.p.

动物药代数据
Animal Mice^[3]
Dose 5 mg/kg
Administration i.p.
F 0.138
V_d 96.03ml
T_1/2 8.43 h
AUC 3318 ng·h/ml
CL_t 8.32 ml/h

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.2156 mL
- 11.0780 mL
- 22.1561 mL
- 5 mM
- 0.4431 mL
- 2.2156 mL
- 4.4312 mL
- 10 mM
- 0.2216 mL
- 1.1078 mL
- 2.2156 mL

技术信息

CAS号

1597403-47-8

储存条件

粉末: Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C22H24Cl2N2O4

运输

蓝冰

分子量

451.34

别名

trans-ISRIB

溶解度

DMSO	4.0 mg/mL (8.9 mM)
Water	Insoluble
Ethanol	Insoluble

动物实验配方

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N,N'-(trans-cyclohexane-1,4-diyl)bis(2-(4-chlorophenoxy)acetamide) Catalog No. CSN17942

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