Cargando…

Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases

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 t...

Descripción completa

Detalles Bibliográficos
Autores principales: Miao, Mengqiu, Wu, Mengqiu, Li, Yuting, Zhang, Lingge, Jin, Qianqian, Fan, Jiaojiao, Xu, Xinyue, Gu, Ran, Hao, Haiping, Zhang, Aihua, Jia, Zhanjun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8908211/
https://www.ncbi.nlm.nih.gov/pubmed/35281917
http://dx.doi.org/10.3389/fphar.2022.837249
_version_ 1784665829362630656
author Miao, Mengqiu
Wu, Mengqiu
Li, Yuting
Zhang, Lingge
Jin, Qianqian
Fan, Jiaojiao
Xu, Xinyue
Gu, Ran
Hao, Haiping
Zhang, Aihua
Jia, Zhanjun
author_facet Miao, Mengqiu
Wu, Mengqiu
Li, Yuting
Zhang, Lingge
Jin, Qianqian
Fan, Jiaojiao
Xu, Xinyue
Gu, Ran
Hao, Haiping
Zhang, Aihua
Jia, Zhanjun
author_sort Miao, Mengqiu
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8908211
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-89082112022-03-11 Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases Miao, Mengqiu Wu, Mengqiu Li, Yuting Zhang, Lingge Jin, Qianqian Fan, Jiaojiao Xu, Xinyue Gu, Ran Hao, Haiping Zhang, Aihua Jia, Zhanjun Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2022-02-24 /pmc/articles/PMC8908211/ /pubmed/35281917 http://dx.doi.org/10.3389/fphar.2022.837249 Text en Copyright © 2022 Miao, Wu, Li, Zhang, Jin, Fan, Xu, Gu, Hao, Zhang and Jia. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Miao, Mengqiu
Wu, Mengqiu
Li, Yuting
Zhang, Lingge
Jin, Qianqian
Fan, Jiaojiao
Xu, Xinyue
Gu, Ran
Hao, Haiping
Zhang, Aihua
Jia, Zhanjun
Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases
title Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases
title_full Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases
title_fullStr Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases
title_full_unstemmed Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases
title_short Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases
title_sort clinical potential of hypoxia inducible factors prolyl hydroxylase inhibitors in treating nonanemic diseases
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8908211/
https://www.ncbi.nlm.nih.gov/pubmed/35281917
http://dx.doi.org/10.3389/fphar.2022.837249
work_keys_str_mv AT miaomengqiu clinicalpotentialofhypoxiainduciblefactorsprolylhydroxylaseinhibitorsintreatingnonanemicdiseases
AT wumengqiu clinicalpotentialofhypoxiainduciblefactorsprolylhydroxylaseinhibitorsintreatingnonanemicdiseases
AT liyuting clinicalpotentialofhypoxiainduciblefactorsprolylhydroxylaseinhibitorsintreatingnonanemicdiseases
AT zhanglingge clinicalpotentialofhypoxiainduciblefactorsprolylhydroxylaseinhibitorsintreatingnonanemicdiseases
AT jinqianqian clinicalpotentialofhypoxiainduciblefactorsprolylhydroxylaseinhibitorsintreatingnonanemicdiseases
AT fanjiaojiao clinicalpotentialofhypoxiainduciblefactorsprolylhydroxylaseinhibitorsintreatingnonanemicdiseases
AT xuxinyue clinicalpotentialofhypoxiainduciblefactorsprolylhydroxylaseinhibitorsintreatingnonanemicdiseases
AT guran clinicalpotentialofhypoxiainduciblefactorsprolylhydroxylaseinhibitorsintreatingnonanemicdiseases
AT haohaiping clinicalpotentialofhypoxiainduciblefactorsprolylhydroxylaseinhibitorsintreatingnonanemicdiseases
AT zhangaihua clinicalpotentialofhypoxiainduciblefactorsprolylhydroxylaseinhibitorsintreatingnonanemicdiseases
AT jiazhanjun clinicalpotentialofhypoxiainduciblefactorsprolylhydroxylaseinhibitorsintreatingnonanemicdiseases