Phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) helps to prevent the accumulation of misfolded proteins in the endoplasmic reticulum by decreasing protein synthesis; this phosphorylation is removed by a complex composed of the phosphatase PP1c and its regulatory subunit PPP1R15A. Although the compound guanabenz (GBZ) inhibits PPP1R15A–PP1c, it is unsuitable for in vivo use, as it has affinity for the α2-adrenergic receptor. Das et al. show that the GBZ derivative Sephin1 overcomes this limitation. Sephin1 bound to PPP1R15A, but not to PPP1R15B, in vitro and disrupted PPP1R15A–PP1c, but not PPP1R15B–PP1c, in vivo, validating its specificity. Importantly, Sephin1 has no affinity for the α2-adrenergic receptor, and mice treated with it do not show the side effects associated with GBZ. Instead, Sephin1 reversed disease symptoms in mouse models of two protein-misfolding diseases — Charcot–Marie–Tooth 1B and amyotrophic lateral sclerosis.