Therapeutic targeting of the HIF oxygen-sensing pathway: Lessons learned from clinical studies

Abstract

The oxygen-sensitive hypoxia-inducible factor (HIF) pathway plays a central role in the control of erythropoiesis and iron metabolism. The discovery of prolyl hydroxylase domain (PHD) proteins as key regulators of HIF activity has led to the development of inhibitory compounds that are now in phase 3 clinical development for the treatment of renal anemia, a condition that is commonly found in patients with advanced chronic kidney disease. This review provides a concise overview of clinical effects associated with pharmacologic PHD inhibition and was written in memory of Professor Lorenz Poellinger.

Keywords: Anemia; Chronic kidney disease; Clinical trials; Hypoxia; Hypoxia-inducible factor; Oxygen; Prolyl hydroxylase domain.

Figure 1. Overview of the HIF oxygen-sensing pathway

Although the oxygen-sensitive HIF-α subunit is constitutively synthesized, it is rapidly degraded under normoxic conditions. Under hypoxia, however, cellular HIF-α levels build up and HIF-α translocates to the nucleus, where it forms a heterodimer with HIF-β. Proteasomal degradation of HIF-α is mediated by the pVHL-E3-ubiquitin ligase complex and requires HIF-α prolyl-4-hydroxylation by oxygen- and iron-dependent PHD enzymes (PHD1-3). The decarboxylation of 2-oxoglutarate (2OG) produces hydroxylated HIF-α, succinate and CO₂. A reduction in PHD catalytic activity (e.g. due to hypoxia or pharmacologic inhibition) results in increased transcription of HIF-regulated genes such as vascular endothelial growth factor (VEGF), erythropoietin (EPO), phosphoglycerate kinase 1 (PGK1), lactate dehydrogenase (LDH) and other genes involved in the regulation of hypoxia responses. Shown are the chemical structures of three PHD inhibitors (PHI), which are now in phase 3 clinical development for renal anemia. A common characteristic of daprodustat, roxadustat and vadadustat is a carbonylglycine side chain that is structurally analogous to 2OG.