Chemical development of a cyclic peptide protein-protein interaction inhibitor.

The rapid growth of tumours results in their outstripping of the supply of oxygen and nutrients delivered by the existing vascular network. As a result, tumours need to adapt to hypoxia (low environmental oxygen). This process is primarily mediated through the hypoxia inducible factor (HIF-1), a heterodimeric transcription factor composed of an alpha and beta subunit that alters the expression of over 300 genes in response to the onset of hypoxia. A second isoform, HIF-2alpha also binds to HIF-1beta and is thought to adaptation to long term hypoxia.

This project aims to use the tools of medicinal chemistry to optimise a series of cyclic peptide HIF-1 and HIF-2 inhibitors towards the clinic. We will synthesize a series of non-natural analogues of the leading hit molecule. The potency of these molecules will be assessed by a variety of biophysical techniques, and these results will in turn inform on the structure of additional molecules in an attempt to increase potency. We will also attempt to obtain structural data on the peptide/protein complex to enable design of small molecule inhibitors binding into the same pocket. By taking this two-pronged approach, we hope to develop the next generation of potent, small molecule HIF inhibitors.