Prolyl hydroxylase domain-containing protein inhibitors as stabilizers of hypoxia-inducible factor: small molecule-based therapeutics for anemia

Abstract

Importance of the field: Anemia caused by chronic kidney disease and other chronic diseases or conditions can be managed by the treatment of biologic-based erythropoiesis stimulating agents (ESAs). Although these ESAs are successful in treating these anemic conditions, a small molecule-based anti-anemia medicine can potentially revolutionize the treatment of anemia by bringing convenience to patients and being cost effective. Prolyl hydroxylase domain-containing protein (PHD) inhibitors may provide an opportunity for the development of small molecule anti-anemia medicines.

Areas covered in this review: This review covers efforts to target PHD enzymes for stabilization of hypoxia-inducible factor (HIF)-α subunits under normal oxygen levels as an attractive strategy to upregulate the expression of erythropoietin and genes involved in iron metabolism for the treatment of anemia.

What the reader will gain: The reader will gain a brief summary of recent advances in HIF and PHD biology and a review of patents/patent applications on the subject of PHD inhibitors as HIF stabilizers for the treatment of anemia.

Take home message: Several classes of PHD enzyme inhibitors have been disclosed and several are currently in clinical trials for the development of small molecule-based therapeutics for the treatment of anemia.

Keywords::

• anemia
• erythropoiesis stimulating agents
• erythropoietin
• factor inhibiting HIF
• prolyl hydroxylase domain-containing protein

Acknowledgement

The authors thank Qun Dang, John S Debenham, Songnian Lin, Edward C Sherer and Dominique Stickens for useful discussions and comments about the manuscript and Sharon M O'Brien of Research Communications at Merck Research Laboratories for creating Figure 1.

Notes

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