Recent advance of hypoxia-inducible factor prolyl hydroxylases inhibitors for anemia therapy

Abstract

Recent advancements in prolyl hydroxylase domain enzyme (PHD) inhibitors have revolutionized anemia treatment by targeting hypoxia-inducible factor (HIF) pathways. Initially, PHD enzymes were identified as critical regulators of HIF-α degradation under normoxia. The discovery of PHD inhibitors emerged from understanding their role in stabilizing HIF-α, which stimulates erythropoietin (EPO) production and iron metabolism, addressing anemia pathophysiology. Early inhibitors, such as FG-2216, demonstrated proof-of-concept but faced safety concerns, prompting structural optimization to enhance selectivity and pharmacokinetic profiles. Subsequent generations, exemplified by roxadustat, incorporated modifications to reduce off-target effects and improve oral bioavailability, achieving clinical efficacy in renal anemia. Optimization strategies focused on balancing potency, tissue specificity, and minimizing adverse effects. The iterative discovery-to-optimization process underscores the value of PHD inhibitors as templates for novel therapies targeting hypoxia-responsive diseases, while ongoing research addresses challenges in long-term safety and patient-specific response variability. This progress solidifies PHD inhibitors as pivotal tools for anemia management and broader therapeutic innovation.