Background
Trans-integrated stress response inhibitor (trans-ISRIB) is a small-molecule inhibitor of the cellular integrated stress response (ISR). The ISR is a coordinated collection of signaling pathways that activate different eukaryotic initiation factor 2 (eIF2) kinases to phosphorylate the subunit eIF2α. trans-ISRIB strongly (IC50 = 5 nM) reverses the effects of eIF2α phosphorylation in cells undergoing ISR (1). Phosphorylation of eIF2α stabilizes and inhibits turnover of the eIF2β protein complex (2). Both trans-ISRIB and eIF2(αP) bind to distinct sites within the guanine nucleotide exchange factor eIF2β. trans-ISRIB inhibits the ISR by promoting eIF2β nucleotide exchange activity and antagonizing the inhibitory effect of eIF2(αP) on eIF2β activity. Simultaneous binding of eIF2(αP) to eIF2β regulatory sites deforms the trans-ISRIB-binding pocket and prevents trans-ISRIB inhibition of the ISR (3). Because heightened ISR is sometimes associated with unfavorable outcomes, trans-ISRIB treatment can provide beneficial effects in models of neurodegeneration, chronic demyelination, and head injury (4-6).
- Sidrauski, C. et al. (2013) Elife 2, e00498.
- Pavitt, G.D. (2005) Biochem Soc Trans 33, 1487-92.
- Zyryanova, A.F. et al. (2021) Mol Cell 81, 88-103.e6.
- Halliday, M. et al. (2015) Cell Death Dis 6, e1672.
- Wong, Y.L. et al. (2018) Elife 7, e32733. doi: 10.7554/eLife.32733.
- Chou, A. et al. (2017) Proc Natl Acad Sci U S A 114, E6420-E6426.
Molecular Formula
C22H24Cl2N2O4
Molecular Weight
451.3 g/mol
Purity
>98%
CAS
1597403-47-8
Solubility
Soluble in DMSO at 5 mg/mL.
Storage
Directions for Use
Background References
Cross-Reactivity Key
H: human M: mouse R: rat Hm: hamster Mk: monkey Vir: virus Mi: mink C: chicken Dm: D. melanogaster X: Xenopus Z: zebrafish B: bovine Dg: dog Pg: pig Sc: S. cerevisiae Ce: C. elegans Hr: horse GP: Guinea Pig Rab: rabbit All: all species expected
Trademarks and Patents
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