Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases

Abstract

Hypoxia inducible factors (HIFs) and their regulatory hydroxylases the prolyl hydroxylase domain enzymes (PHDs) are the key mediators of the cellular response to hypoxia. HIFs are normally hydroxylated by PHDs and degraded, while under hypoxia, PHDs are suppressed, allowing HIF-α to accumulate and transactivate multiple target genes, including erythropoiesis, and genes participate in angiogenesis, iron metabolism, glycolysis, glucose transport, cell proliferation, survival, and so on. Aiming at stimulating HIFs, a group of small molecules antagonizing HIF-PHDs have been developed. Of these HIF-PHDs inhibitors (HIF-PHIs), roxadustat (FG-4592), daprodustat (GSK-1278863), vadadustat (AKB-6548), molidustat (BAY 85-3934) and enarodustat (JTZ-951) are approved for clinical usage or have progressed into clinical trials for chronic kidney disease (CKD) anemia treatment, based on their activation effect on erythropoiesis and iron metabolism. Since HIFs are involved in many physiological and pathological conditions, efforts have been made to extend the potential usage of HIF-PHIs beyond anemia. This paper reviewed the progress of preclinical and clinical research on clinically available HIF-PHIs in pathological conditions other than CKD anemia.

Risk of infection in roxadustat treatment for anemia in patients with chronic kidney disease: A systematic review with meta-analysis and trial sequential analysis

“…Over 20 clinical trials have demonstrated that roxadustat can effectively improve anemia in patients with CKD by increasing Hb levels and regulating iron metabolism, and studies suggested that roxadustat may be available in more pathological conditions (Miao et al, 2022). The lack of real-world safety data is an obstacle to broader acceptance.…”

Deferiprone: A Forty-Year-Old Multi-Targeting Drug with Possible Activity against COVID-19 and Diseases of Similar Symptomatology

“…Hydroxylation appears to be the main regulator of HIFα subunit protein stability and is controlled by HIF prolyl hydroxylases (HIF PHD) [ 146 ]. One of the major targeting prospects of iron chelators in relation to hypoxia in COVID-19 is their ability to inhibit HIF PHD, which are non-hem iron-containing dioxygenases [ 147 , 148 , 149 ]. In this context and many other cases of iron-containing enzymes, iron removal or displacement by chelators can reduce the activity of HIF PHD and increase the anti-hypoxic response, thus improving the hypoxic state of COVID-19 patients [ 150 ].…”

Anemia on Chronic Kidney Disease: The Role of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors

“…7 The Prolyl hydroxylase domain enzymes (PHD) 1-3 and an asparaginyl hydroxylase (factorinhibiting HIF, or FIH) regulate the HIF Pathway. 15…”

“…13 Prolyl hydroxylase domain (PHD) enzymes, also known as HIF-prolyl hydroxylases (HPHs), use molecular oxygen as their substrate to hydroxylate proteins. 15 Under adequate oxygen levels, HIF-α is continuously produced and promptly degraded by PHDs via hydroxylation. 16 Von Hippel-Lindau (vHL) mediates this degradation, followed by ubiquitination and proteasomal destruction.…”

“…17, 18 Hypoxia lowers the enzymatic activity of PHDs, this situation allows HIF-α to accumulate and transactivate multiple target genes, such as those involved in erythropoiesis, angiogenesis, iron metabolism, and glycolysis, glucose transport, cell proliferation, and survival. 15 The accumulation of HIF formed a heterodimer with HIF-α. 19 This heterodimer subsequently moves to the nucleus, and then continues binded to hypoxia-responsive elements (HRE), activating EPO synthesis in the kidneys and liver.…”