Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is one of the RNA-binding proteins, which plays key roles in the regulation of RNA metabolism and stability. Previous study shows that Moracin-O derivative MO-460 inhibit HIF-1α translation under hypoxia conditions by binding to hnRNPA2B1 preventing it from binding to HIF-1α mRNA. Herein, a SAR study with modifications on the chiral rings of moracins O and P, identified a novel chiral-free benzofuran derivative MO-2097 with reduced structural complexity and increased efficiency. MO-2097 reduced HIF-1α accumulation by directly binding to hnRNPA2B1, decreasing HIF-1α target gene mRNA levels. Furthermore, MO-2097 showed in vivo efficacy, without significant toxicity, in mouse xenograft models. Additionally, MO-2097 works effectively in cancer patient-based organoid models, especially those having in higher hnRNPA2B1 and HIF-1α levels. Synthesis and SAR studies of MO-2097 derivatives are under progress.