eIF2α Activator 2

eIF2α activator 2 is an activator of eukaryotic translation initiation factor 2α kinase 1 (EIF2AK1), also known as heme-regulated inhibitor kinase (HRI).¹ It activates HRI and induces eIF2α phosphorylation in a surrogate cell-based reporter assay. eIF2α activator 2 selectively inhibits the proliferation of CRL-2813 melanoma cells (IC₅₀ = 0.46 µM) over non-cancerous NIH3T3 fibroblasts (IC₅₀ = 3.4 µM). It also selectively inhibits the proliferation of CRL-2813 cells transiently transfected with non-targeted siRNA (IC₅₀ = 0.66 µM) over those transiently transfected with HRI-targeted siRNA (IC₅₀ = 5 µM). eIF2α activator 2 (5 µM) increases mRNA expression and protein levels of the eIF2α target DNA damage-inducible transcript 3 (DDIT3), also known as C/EBP homologous protein (CHOP), in CRL-2813 cells.²

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1. Chen, T., Takrouri, K., Hee-Hwang, S., et al. Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase. J. Med. Chem. 56(23), 9457-9470 (2013).

2. Yefidoff-Freedman, R., Fan, J., Yan, L., et al. Development of 1-((1,4-trans)-4-aryloxycyclohexyl)-3-arylurea activators of heme-regulated inhibitor as selective activators of the eukaryotic initiation factor 2 alpha (EIF_2α) phosphorylation arm of the integrated endoplasmic reticulum stress response. J. Med. Chem. 60(13), 5392-5406 (2017).