Targeting Protein-Protein Interactions in the HIF System

What is it about?

Animals respond to chronic hypoxia by increasing the levels of a transcription factor known as the hypoxia-inducible factor (HIF). HIF upregulates multiple genes, the products of which work to ameliorate the effects of limited oxygen at cellular and systemic levels. Hypoxia sensing by the HIF system involves hydroxylase-catalysed post-translational modifications of the HIF α-subunits, which 1) signal for degradation of HIF-α and 2) limit binding of HIF to transcriptional coactivator proteins. Because the hypoxic response is relevant to multiple disease states, therapeutic manipulation of the HIF-mediated response has considerable medicinal potential. In addition to modulation of catalysis by the HIF hydroxylases, the HIF system manifests other possibilities for therapeutic intervention involving protein–protein and protein–nucleic acid interactions. Recent advances in our understanding of the structural biology and biochemistry of the HIF system are facilitating medicinal chemistry efforts. Herein we give an overview of the HIF system, focusing on structural knowledge of protein–protein interactions and how this might be used to modulate the hypoxic response for therapeutic benefit.

Featured Image

Why is it important?

Work over the last 15 years or so has led to the discovery that specific protein-protein interactions play central roles in hypoxic sensing in humans and animals. Considerable progress has been made towards developing chemically useful inhibitors of the sets of enzymes underlying HIF-α hydroxylation, i.e. the PHDs, and in demonstrating that disrupting the interactions between prolyl hydroxylated HIF-α and pVHL is a tractable target for small molecules. There remains considerable scope for the development of new types of PHD inhibitor and other compounds that bind to pVHL; in the latter case, the identification of compounds that do not contain a hydroxyproline residue is of interest. It is also likely, due to its HIF-independent roles, that new challenges in pharmaceutical targeting of pVHL will become apparent as compounds are progressed into animal models. Interestingly, this work has helped stimulate the use of small molecules to rationally target proteins for ‘catalytic’ degradation of protein targets rather than just inhibiting by tight binding. The HIF-α:FIH and CBP/p300 interactions are seemingly even more challenging due to the apparently HIF-independent roles of FIH and, in particular, of CBP/p300; hence, these may require long-term studies involving both chemical and biological methods. Finally, although at an early stage, use of biophysical insights to guide the development of compounds that bind to and regulate the activity of the intact HIF:HRE complex in order to alter the kinetics of transcription is a particularly exciting field, especially in light of new structural information.