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Discovery and characterization of a novel HIF-2α agonist for the treatment of CKD-related renal anemia

文献类型：期刊论文

作者Chu, Shu-qing1,6; Chen, Yi-jie1,6; Yang, Rui-rui4,5; Teng, Dan5,6; Zhou, Gui-zhen3,6; Zhang, Ying-ying2,6; Niu, Bu-ying5,6; Xu, Jia-hang4,5,6; Lin, Ke-xin1,6; Yang, Xin-yu1,6
刊名ACTA PHARMACOLOGICA SINICA
出版日期2025-10-01
页码14
关键词anemia HIF-2 alpha aryl hydrocarbon receptor nuclear translocator erythropoietin amide thiazole AT-1 Molidustat M1002
ISSN号1671-4083
DOI10.1038/s41401-025-01657-w
英文摘要Hypoxia-inducible factor 2-alpha (HIF-2 alpha), 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-2 alpha with a KD of 2.63 mu M, and enhanced the stability of the HIF-2 alpha-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-2 alpha. Pharmacological studies showed that AT-1 (10, 20, 40 mu M) 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 mu M) exhibited favorable safety profiles and, when combined with the prolyl hydroxylase (PHD) inhibitor Molidustat (10 mu M), effectively mitigated doxorubicin-induced anemia. In adenine-induced chronic kidney disease (CKD) mouse model, combined administration of AT-1 (50 mgkg-1d-1, i.p.) and Molidustat (10 mgkg-1d-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.
WOS关键词KIDNEY-DISEASE ; STRUCTURAL BASIS ; HYPOXIA ; ERYTHROPOIETIN ; INTERFERENCE ; FAMILY ; DOMAIN ; GENE
资助项目National Key Research and Development Program of China[2022YFC3400504] ; National Key Research and Development Program of China[2023YFC2305904] ; National Natural Science Foundation of China[T2225002] ; National Natural Science Foundation of China[82273855] ; National Natural Science Foundation of China[82474143] ; National Natural Science Foundation of China[82304379] ; National Natural Science Foundation of China[82204278] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0830200] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB1260301] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0830203] ; Youth Innovation Promotion Association CAS[2023296] ; Youth Innovation Promotion Association CAS[LGL-8888] ; Natural Science Foundation of Shanghai[22ZR1474300] ; Young Elite Scientists Sponsorship Program by CAST[2023QNRC001]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001585058700001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/321591]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Li, Xu-tong; Zheng, Ming-yue; Zhang, Su-lin
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Univ Sci & Technol China, Sch Life Sci, Div Life Sci & Med, Hefei 230026, Peoples R China
3.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Chu, Shu-qing,Chen, Yi-jie,Yang, Rui-rui,et al. Discovery and characterization of a novel HIF-2α agonist for the treatment of CKD-related renal anemia[J]. ACTA PHARMACOLOGICA SINICA,2025:14.
APA Chu, Shu-qing.,Chen, Yi-jie.,Yang, Rui-rui.,Teng, Dan.,Zhou, Gui-zhen.,...&Zhang, Su-lin.(2025).Discovery and characterization of a novel HIF-2α agonist for the treatment of CKD-related renal anemia.ACTA PHARMACOLOGICA SINICA,14.
MLA Chu, Shu-qing,et al."Discovery and characterization of a novel HIF-2α agonist for the treatment of CKD-related renal anemia".ACTA PHARMACOLOGICA SINICA (2025):14.

入库方式： OAI收割

来源：上海药物研究所

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