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).

C₂₂H₂₄Cl₂N₂O₄

>98%

1597403-47-8

Soluble in DMSO at 5 mg/mL.

trans-ISRIB is supplied as a lyophilized powder. For a 10 mM stock, reconstitute 5 mg of powder in 1.11 mL of DMSO. Working concentrations and length of treatment can vary depending on the desired effect.