Frontiers in Pharmacology (Feb 2022)
Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases
- Mengqiu Miao,
- Mengqiu Miao,
- Mengqiu Miao,
- Mengqiu Wu,
- Mengqiu Wu,
- Mengqiu Wu,
- Yuting Li,
- Yuting Li,
- Yuting Li,
- Lingge Zhang,
- Lingge Zhang,
- Lingge Zhang,
- Qianqian Jin,
- Qianqian Jin,
- Qianqian Jin,
- Jiaojiao Fan,
- Jiaojiao Fan,
- Jiaojiao Fan,
- Jiaojiao Fan,
- Xinyue Xu,
- Xinyue Xu,
- Xinyue Xu,
- Xinyue Xu,
- Ran Gu,
- Ran Gu,
- Ran Gu,
- Haiping Hao,
- Aihua Zhang,
- Aihua Zhang,
- Aihua Zhang,
- Zhanjun Jia,
- Zhanjun Jia,
- Zhanjun Jia
Affiliations
- Mengqiu Miao
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Mengqiu Miao
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Mengqiu Miao
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Mengqiu Wu
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Mengqiu Wu
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Mengqiu Wu
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Yuting Li
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Yuting Li
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Yuting Li
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Lingge Zhang
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Lingge Zhang
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Lingge Zhang
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Qianqian Jin
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Qianqian Jin
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Qianqian Jin
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Jiaojiao Fan
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Jiaojiao Fan
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Jiaojiao Fan
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Jiaojiao Fan
- School of Medicine, Southeast University, Nanjing, China
- Xinyue Xu
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Xinyue Xu
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Xinyue Xu
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Xinyue Xu
- School of Medicine, Southeast University, Nanjing, China
- Ran Gu
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Ran Gu
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Ran Gu
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Haiping Hao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing, China
- Aihua Zhang
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Aihua Zhang
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Aihua Zhang
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Zhanjun Jia
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Zhanjun Jia
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Zhanjun Jia
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- DOI
- https://doi.org/10.3389/fphar.2022.837249
- Journal volume & issue
-
Vol. 13
Abstract
Hypoxia inducible factors (HIFs) and their regulatory hydroxylases the prolyl hydroxylase domain enzymes (PHDs) are the key mediators of the cellular response to hypoxia. HIFs are normally hydroxylated by PHDs and degraded, while under hypoxia, PHDs are suppressed, allowing HIF-α to accumulate and transactivate multiple target genes, including erythropoiesis, and genes participate in angiogenesis, iron metabolism, glycolysis, glucose transport, cell proliferation, survival, and so on. Aiming at stimulating HIFs, a group of small molecules antagonizing HIF-PHDs have been developed. Of these HIF-PHDs inhibitors (HIF-PHIs), roxadustat (FG-4592), daprodustat (GSK-1278863), vadadustat (AKB-6548), molidustat (BAY 85-3934) and enarodustat (JTZ-951) are approved for clinical usage or have progressed into clinical trials for chronic kidney disease (CKD) anemia treatment, based on their activation effect on erythropoiesis and iron metabolism. Since HIFs are involved in many physiological and pathological conditions, efforts have been made to extend the potential usage of HIF-PHIs beyond anemia. This paper reviewed the progress of preclinical and clinical research on clinically available HIF-PHIs in pathological conditions other than CKD anemia.
Keywords
- hypoxia inducible factors (HIFs)
- HIF-PHDs inhibitors (HIF-PHIs)
- nonanemic diseases
- roxadustat (FG-4592)
- daprodustat (GSK-1278863)
- vadadustat (AKB-6548)
