Targeting hypoxia-inducible factors: therapeutic opportunities and challenges

被引:0
作者
Xiaoyi Yuan
Wei Ruan
Bentley Bobrow
Peter Carmeliet
Holger K. Eltzschig
机构
[1] The University of Texas Health Science Center at Houston,Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School
[2] Central South University,Department of Anaesthesiology, The Second Xiangya Hospital
[3] The University of Texas Health Science Center at Houston,Department of Emergency Medicine, McGovern Medical School
[4] KU Leuven,Laboratory of Angiogenesis & Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology
[5] Aarhus University,Laboratory of Angiogenesis & Vascular Heterogeneity, Department of Biomedicine
[6] Khalifa University of Science and Technology,Center for Biotechnology
[7] Outcomes Research Consortium,undefined
来源
Nature Reviews Drug Discovery | 2024年 / 23卷
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摘要
Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that are crucial for adaptation of metazoans to limited oxygen availability. Recently, HIF activation and inhibition have emerged as therapeutic targets in various human diseases. Pharmacologically desirable effects of HIF activation include erythropoiesis stimulation, cellular metabolism optimization during hypoxia and adaptive responses during ischaemia and inflammation. By contrast, HIF inhibition has been explored as a therapy for various cancers, retinal neovascularization and pulmonary hypertension. This Review discusses the biochemical mechanisms that control HIF stabilization and the molecular strategies that can be exploited pharmacologically to activate or inhibit HIFs. In addition, we examine medical conditions that benefit from targeting HIFs, the potential side effects of HIF activation or inhibition and future challenges in this field.
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页码:175 / 200
页数:25
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共 511 条
[81]  
Eltzschig HK(1999)HIF-alpha prolyl hydroxylase inhibitors and their implications for biomedicine: a comprehensive review Proc. Natl Acad. Sci. USA 96 10296-1464
[82]  
Bratton DL(2005)The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis Biochem. Biophys. Res. Commun. 338 5223-3048
[83]  
Colgan SP(2005)Identification of the von Hippel–Lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex EMBO J. 24 167-1932
[84]  
Hatfield SM(2005)Signalling hypoxia by HIF hydroxylases Sci. STKE 2005 8-1603
[85]  
Lee JW(2008)Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression Gastroenterology 134 727-2055
[86]  
Ko J(2004)Integration of oxygen signaling at the consensus HRE J. Biol. Chem. 279 1462-2324
[87]  
Ju C(2017)Hypoxia-independent activation of HIF-1 by Enterobacteriaceae and their siderophores Chem. Sci. 8 3039-2335
[88]  
Eltzschig HK(2015)Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor J. Biol. Chem. 290 407-354
[89]  
Ong SG(2007)Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials Crit. Rev. Oncol. Hematol. 64 1926-907
[90]  
Guo Y(1998)Protein hydroxylation catalyzed by 2-oxoglutarate-dependent oxygenases Blood 92 1596-1163