HIF-PHI Therapy
FibroGen is focused on the discovery and development of small molecules that stabilize HIF through the inhibition of HIF prolyl hydroxylase (HIF-PH) enzymes. Research conducted by FibroGen and others suggests that pharmacological manipulation of HIF biology will be effective in treating a wide range of diseases.
The HIF transcription factor is a heterodimer comprised of two protein subunits, HIF-α and HIF-β. The HIF-α/β heterodimer binds specific sequences of DNA in the nucleus, leading to the activation or suppression of hypoxia-responsive genes. HIF-β is constitutively present, whereas stability of the labile HIF-α subunit is regulated by a family of HIF-PH enzymes.
Under normal oxygen conditions, HIF-PH’s catalyze “prolyl hydroxylation”, an oxygen-dependent chemical reaction that adds a hydroxyl group to two specific proline amino acid residues within the HIF-α subunit. The result of hydroxylation is that HIF-α is degraded, and the HIF-α/β heterodimer does not form.In contrast, under hypoxic conditions, or using small molecule inhibitors of HIF-PH (even in normoxic conditions), prolyl hydroxylation is suppressed and HIF-α accumulates to high levels, enabling heterodimer formation, translocation to the nucleus and binding to specific DNA sequences located on hypoxia-responsive genes.
Using HIF-PH Inhibitors (HIF-PHI) to Selectively Modulate HIF-Mediated Gene Activity
Because oxygen homeostasis is complex — too much oxygen can be as detrimental as too little oxygen — the HIF system has many points of control, which enable the body to fine-tune and integrate systemic and cellular responses to hypoxia. For instance, there are three known isoforms of HIF-α (HIF-1, HIF-2, and HIF-3) and three types of HIF-PH isoenzymes. HIF-α isoforms have been associated with different activities. For example, the HIF-2 isoform has a predominant role in activating the gene encoding erythropoietin, whereas the HIF-1 isoform has a predominant role in vasculogenesis. FibroGen's research demonstrates that the three known HIF-PH isoenzymes exhibit unique expression patterns in various cells and organs. It appears that each HIF-PH isoenzyme has a different affinity for the proline hydroxylation sites found on different HIF-α isoforms. For example, the HIF-PH2 isoenzyme has been reported to control HIF-1 stabilization.
Just as the body is able to fine-tune its response to tissue hypoxia, the inherent complexity of the HIF system also lends itself to selective manipulation with HIF-PHI. FibroGen and collaborators are actively investigating the specific physiologies controlled by each of the HIF-PH isoenzymes and HIF isoforms to advance the therapeutic potential of HIF-PHI for a wide variety of diseases. Having the largest collection of HIF-PHI in the world, FibroGen is uniquely positioned to lead the industry in this exciting new field of drug discovery.
FibroGen has HIF-PHI development programs in Anemia and Cytoprotection/Inflammation.
