摘要Hypoxia-inducible factor 2-alpha(HIF-2α),a critical transcription factor,forms a heterodimer with aryl hydrocarbon receptor nuclear translocator(ARNT)to drive the transcription of erythropoietin(EPO),a key regulator of erythropoiesis.Activation of this pathway plays a pivotal role in the treatment of anemia.By discovered structure-based virtual screening and pharmacological assays,we herein discovered an amide thiazole AT-1 that bound to HIF-2α with a KD of 2.63 μM,and enhanced the stability of the HIF-2α-ARNT heterodimer.Molecular docking and site-directed mutagenesis analysis revealed the critical roles of His293 and Tyr307 in the binding of AT-1 to HIF-2α.Pharmacological studies showed that AT-1(10,20,40 μM)dose-dependently enhanced both the transcription and secretion of EPO in 786-O and Hep3B cells.In zebrafish(Danio rerio),AT-1(10 or 50 μM)exhibited favorable safety profiles and,when combined with the prolyl hydroxylase(PHD)inhibitor Molidustat(10 μM),effectively mitigated doxorubicin-induced anemia.In adenine-induced chronic kidney disease(CKD)mouse model,combined administration of AT-1(50 mg·kg-1-d-1,i.p.)and Molidustat(10 mg·kg-1·d-1,i.p.)for 15 days produced stronger effects on increasing EPO levels and alleviating anemia than Molidustat alone,further supporting the therapeutic potential of AT-1 in CKD-related anemia.