IACS-77717

IACS-77717 is a potent, selective, and orally bioavailable small-molecule inhibitor of the heme-regulated inhibitor (HRI) kinase, also known as eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1). Developed by the Institute for Applied Cancer Science (IACS) at MD Anderson Cancer Center, it targets the integrated stress response (ISR) pathway by preventing HRI-mediated phosphorylation of eIF2α on serine 51. In preclinical models of myelodysplastic syndromes with ringed sideroblasts (MDS-RS), IACS-77717 has been shown to rescue ineffective erythropoiesis by increasing the expression of mitochondrial heme transporters and improving terminal erythroid differentiation. In sickle cell disease (SCD), the compound represses BCL11A and increases fetal hemoglobin (HbF) production. IACS-77717 demonstrates high selectivity (650-fold) for HRI over other ISR family members such as PKR, PERK, and GCN2, with a biochemical IC50 of 1.3 nM.