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

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

  • Acta Pharmacol Sin. 2025 Oct 1. doi: 10.1038/s41401-025-01657-w.
Shu-Qing Chu # 1 2,  Yi-Jie Chen # 1 2,  Rui-Rui Yang # 3 4,  Dan Teng 2 3,  Gui-Zhen Zhou 2 5,  Ying-Ying Zhang 2 6,  Bu-Ying Niu 2 3,  Jia-Hang Xu 2 3 4,  Ke-Xin Lin 1 2,  Xin-Yu Yang 1 2,  Xu-Tong Li 7 8,  Ming-Yue Zheng 9 10 11 12 13 14,  Su-Lin Zhang 15 16
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 5 School of Life Science and Technology, Shanghai Tech University, Shanghai, 201210, China.
  • 6 School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
  • 7 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. lixutong@simm.ac.cn.
  • 8 University of Chinese Academy of Sciences, Beijing, 100049, China. lixutong@simm.ac.cn.
  • 9 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China. myzheng@simm.ac.cn.
  • 10 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. myzheng@simm.ac.cn.
  • 11 University of Chinese Academy of Sciences, Beijing, 100049, China. myzheng@simm.ac.cn.
  • 12 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. myzheng@simm.ac.cn.
  • 13 School of Life Science and Technology, Shanghai Tech University, Shanghai, 201210, China. myzheng@simm.ac.cn.
  • 14 School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China. myzheng@simm.ac.cn.
  • 15 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. slzhang@simm.ac.cn.
  • 16 University of Chinese Academy of Sciences, Beijing, 100049, China. slzhang@simm.ac.cn.
  • # Contributed equally.
PMID: 41034402 DOI: 10.1038/s41401-025-01657-w
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.

Keywords

HIF-2α; M1002; Molidustat; amide thiazole AT-1; anemia; aryl hydrocarbon receptor nuclear translocator; erythropoietin.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z