HIF inhibitors are medications that modulate the body’s response to oxygen levels. They influence fundamental biological processes, opening new avenues for treating conditions where oxygen sensing pathways are disrupted.
What HIF Is
Hypoxia-Inducible Factor (HIF) is a protein complex that acts as a sensor for oxygen levels within cells. Under normal oxygen conditions, HIF-alpha subunits are continuously produced and then rapidly broken down through a process involving specific enzymes called prolyl hydroxylase domain (PHD) proteins. These PHD enzymes add hydroxyl groups to HIF-alpha, marking it for degradation by the cell’s machinery. This ensures that HIF activity remains low when oxygen is plentiful.
When oxygen levels drop, a state known as hypoxia, the PHD enzymes become less active because they require oxygen to function. This reduced activity prevents the hydroxylation of HIF-alpha, allowing it to accumulate within the cell. The stabilized HIF-alpha then moves into the cell’s nucleus, where it combines with another protein, HIF-beta, to form an active transcription factor. This activated HIF complex binds to specific DNA sequences, turning on a wide array of genes that help the cell and body adapt to low oxygen. These genes are involved in processes such as the formation of new blood vessels, red blood cell production, and changes in metabolism to allow cells to survive with less oxygen.
In certain disease states, HIF can become overactive even when oxygen levels are normal, leading to harmful effects. For instance, in some cancers, persistently high HIF activity can promote the growth of new blood vessels that feed tumors, supporting their survival and spread. In chronic kidney disease, damaged kidneys may not produce enough erythropoietin (EPO), a hormone whose production is regulated by HIF, leading to low red blood cell counts, or anemia.
How HIF Inhibitors Function
HIF inhibitors work by interfering with the normal breakdown of HIF-alpha, thereby increasing its levels within cells. Many of these inhibitors specifically target the prolyl hydroxylase domain (PHD) enzymes. By blocking the activity of PHDs, HIF inhibitors prevent the hydroxylation of HIF-alpha, allowing it to accumulate. This accumulation mimics the body’s natural response to low oxygen, even when oxygen levels are adequate.
Once HIF-alpha is stabilized, it moves into the nucleus and activates genes involved in various adaptive responses. This includes increasing the production of erythropoietin (EPO), a hormone that stimulates red blood cell formation.
Approved Uses of HIF Inhibitors
HIF inhibitors have gained approval for treating specific medical conditions, most notably anemia associated with chronic kidney disease (CKD). Patients with CKD often experience anemia because their kidneys, which normally produce erythropoietin (EPO), are damaged and cannot produce enough of this hormone. HIF-prolyl hydroxylase inhibitors (HIF-PHIs) address this by stabilizing HIF, which in turn stimulates the body’s own production of EPO, primarily in the kidneys and liver. This endogenous EPO production helps to correct and maintain hemoglobin levels, offering an oral treatment alternative to traditional injectable erythropoiesis-stimulating agents (ESAs).
Several HIF-PHIs, including roxadustat, daprodustat, and vadadustat, have received approval in various countries for managing renal anemia in both dialysis-dependent and non-dialysis-dependent CKD patients. These drugs have demonstrated effectiveness in raising hemoglobin levels in clinical trials. HIF-PHIs also improve iron metabolism by increasing absorption and utilization, for example, by lowering hepcidin levels to promote better iron availability for red blood cell production.
Another approved application for HIF inhibitors is in the treatment of certain tumors associated with von Hippel-Lindau (VHL) disease. VHL disease is a rare inherited condition where a mutation in the VHL gene leads to a non-functional VHL protein. The VHL protein normally helps degrade HIF-2A under regular oxygen conditions. When impaired, HIF-2A accumulates abnormally, promoting uncontrolled cell growth, new blood vessel formation, and tumor development. Belzutifan, a HIF-2 inhibitor, was approved to treat VHL-associated tumors, including renal cell carcinoma, central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors.
Emerging Areas of Research
Research into HIF inhibitors extends beyond their current approved uses, exploring their potential in various other conditions. Scientists are investigating HIF-PHD inhibitors for their ability to promote HIF stabilization in situations like inflammatory diseases and ischemia-reperfusion injury. For example, studies are underway to assess HIF-PHD inhibitors for treating lung inflammation in patients with acute respiratory distress syndrome (ARDS).
The role of HIF inhibitors in cancer therapy is also an active area of investigation. While HIF activation can promote tumor growth, some HIF inhibitors are being developed to prevent this activation, particularly for cancers where HIF pathways are overactive. Clinical trials are evaluating HIF-2α inhibitors, such as belzutifan, for advanced clear cell renal cell carcinoma and other solid tumors, including pancreatic neuroendocrine tumors and pheochromocytoma/paraganglioma. These inhibitors aim to block the signals that drive tumor growth and blood vessel formation in these cancers.
Beyond cancer, other emerging areas include iron overload disorders, where modulating HIF-2α could offer therapeutic benefits. Additionally, some preclinical studies are exploring the implication of HIF-PHIs in conditions like retinopathy of prematurity and meibomian gland dysfunction, highlighting the diverse biological processes influenced by HIF signaling.