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Annual Review of Pharmacology and Toxicology

Volume 59, 2019

Pharmacologic Targeting of Hypoxia-Inducible Factors

Abstract

Hypoxia-inducible factors (HIFs) control transcriptional responses to reduced O availability. HIFs are heterodimeric proteins composed of an O-regulated HIF-α subunit and a constitutively expressed HIF-1β subunit. HIF-α subunits are subject to prolyl hydroxylation, which targets the proteins for degradation under normoxic conditions. Small molecule prolyl hydroxylase inhibitors, which stabilize the HIF-α subunits and increase HIF-dependent expression of erythropoietin, are in phase III clinical trials for the treatment of anemia in patients with chronic kidney disease. HIFs contribute to the pathogenesis of many cancers, particularly the clear cell type of renal cell carcinoma in which loss of function of the von Hippel-Lindau tumor suppressor blocks HIF-2α degradation. A small molecule inhibitor that binds to HIF-2α and blocks dimerization with HIF-1β is in clinical trials for the treatment of renal cell carcinoma. Targeting HIFs for stabilization or inhibition may improve outcomes in diseases that are common causes of mortality in the US population.

Keyword(s): anemia, cancer, chronic kidney disease, critical limb ischemia, HIF stabilizers, inflammatory bowel disease
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/content/journals/10.1146/annurev-pharmtox-010818-021637
2019-01-06
2024-04-24
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/content/journals/10.1146/annurev-pharmtox-010818-021637
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Pharmacologic Targeting of Hypoxia-Inducible Factors
Annual Review of Pharmacology and Toxicology 59, 379 (2019); https://doi.org/10.1146/annurev-pharmtox-010818-021637
/content/journals/10.1146/annurev-pharmtox-010818-021637
/content/journals/10.1146/annurev-pharmtox-010818-021637
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  • Article Type: Review Article

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