IACS-18148

IACS-18148 is a potent, selective, and orally bioavailable small-molecule inhibitor of the heme-regulated inhibitor (HRI) kinase, also known as 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 the eukaryotic translation initiation factor 2 alpha (eIF2α). In preclinical models of myelodysplastic syndromes with ringed sideroblasts (MDS-RS), IACS-18148 has been shown to rescue ineffective erythropoiesis and improve terminal erythroid differentiation by increasing the expression of mitochondrial heme transporters and globin synthesis. In sickle cell disease (SCD) models, the compound represses BCL11A and induces fetal hemoglobin (HbF) production, suggesting potential therapeutic utility in treating anemia and transfusion dependency.