@article{APS11460,
author = {Shu-qing Chu and Yi-jie Chen and Rui-rui Yang and Dan Teng and Gui-zhen Zhou and Ying-ying Zhang and Bu-ying Niu and Jia-hang Xu and Ke-xin Lin and Xin-yu Yang and Xu-tong Li and Ming-yue Zheng and Su-lin Zhang},
title = {Discovery and characterization of a novel HIF-2α agonist for the treatment of CKD-related renal anemia},
journal = {Acta Pharmacologica Sinica},
volume = {47},
number = {2},
year = {2026},
keywords = {},
abstract = {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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/11460}
}