2BAct
目录号 : GC39800An eIF2B activator
Cas No.:2143542-28-1
Sample solution is provided at 25 µL, 10mM.
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2BAct is an activator of eukaryotic translation initiation factor 2B (eIF2B; EC50 = 33 nM in a reporter assay).1 It enhances eIF2B activity in primary fibroblasts isolated from Eif2b5R191H mutant (R191H) mouse embryos (EC50 = 7.3 nM), a model of vanishing white matter (VWM) leukodystrophy. In vivo, 2BAct (30 mg/kg) normalizes body weight gain and prevents the development of motor deficits in R191H mice. It also prevents activation of the integrated stress response and myelin loss in the same model.
1.Wong, Y.L., LeBon, L.B., A.M., Kohlhaas, K.L., et al.eIF2B activator prevents neurological defects caused by a chronic integrated stress responseeLife8e42949(2019)
Cas No. | 2143542-28-1 | SDF | |
Canonical SMILES | O=C(C(C=N1)=NC=C1C(F)F)NC(C2)(C3)CC23NC(COC(C=C4)=CC(F)=C4Cl)=O | ||
分子式 | C19H16ClF3N4O3 | 分子量 | 440.8 |
溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.2686 mL | 11.343 mL | 22.686 mL |
5 mM | 0.4537 mL | 2.2686 mL | 4.5372 mL |
10 mM | 0.2269 mL | 1.1343 mL | 2.2686 mL |
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eIF2B activator prevents neurological defects caused by a chronic integrated stress response
Elife 2019 Jan 9;8:e42940.PMID:30624206DOI:10.7554/eLife.42940.
The integrated stress response (ISR) attenuates the rate of protein synthesis while inducing expression of stress proteins in cells. Various insults activate kinases that phosphorylate the GTPase eIF2 leading to inhibition of its exchange factor eIF2B. Vanishing White Matter (VWM) is a neurological disease caused by eIF2B mutations that, like phosphorylated eIF2, reduce its activity. We show that introduction of a human VWM mutation into mice leads to persistent ISR induction in the central nervous system. ISR activation precedes myelin loss and development of motor deficits. Remarkably, long-term treatment with a small molecule eIF2B activator, 2BAct, prevents all measures of pathology and normalizes the transcriptome and proteome of VWM mice. 2BAct stimulates the remaining activity of mutant eIF2B complex in vivo, abrogating the maladaptive stress response. Thus, 2BAct-like molecules may provide a promising therapeutic approach for VWM and provide relief from chronic ISR induction in a variety of disease contexts.
Insights into the mechanism of oligodendrocyte protection and remyelination enhancement by the integrated stress response
bioRxiv 2023 Jan 23;2023.01.23.525156.PMID:36747743DOI:10.1101/2023.01.23.525156.
CNS inflammation triggers activation of the integrated stress response (ISR). We previously reported that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation (Chen et al., eLife , 2021). However, the exact mechanisms through which this occurs remain unknown. Here, we investigated whether the ISR modulator Sephin1 in combination with the oligodendrocyte differentiation enhancing reagent bazedoxifene (BZA) is able to accelerate remyelination under inflammation, and the underlying mechanisms mediating this pathway. We find that the combined treatment of Sephin1 and BZA is sufficient to accelerate early-stage remyelination in mice with ectopic IFN-γ expression in the CNS. IFN-γ, which is a critical inflammatory cytokine in multiple sclerosis (MS), inhibits oligodendrocyte precursor cell (OPC) differentiation in culture and triggers a mild ISR. Mechanistically, we further show that BZA promotes OPC differentiation in the presence of IFN-γ, while Sephin1 enhances the IFN-γ-induced ISR by reducing protein synthesis and increasing RNA stress granule formation in differentiating oligodendrocytes. Finally, the ISR suppressor 2BAct is able to partially lessen the beneficial effect of Sephin1 on disease progression, in an MS mouse model of experimental autoimmune encephalitis (EAE). Overall, our findings uncover distinct mechanisms of action of BZA and Sephin1 on oligodendrocyte lineage cells under inflammatory stress, suggesting that a combination therapy may effectively promote restoring neuronal function in MS patients.