Protein-protein interactions (PPIs) represent an emerging target class of critical importance in pharmaceuticals development. This three and a half year project funding two EPSRC funded CASE students integrates synthetic chemistry, biophysics and structural molecular biology with the objective to (1) understand at a structural and biophysical level, helix mediated PPIs of relevance to oncology and (2) design cell permeable small molecule mimetics to target such interactions with high affinity and selectivity. Working in tandem PhD students George Burslem and Hannah Kyle jointly supervised by a multidisciplinary team of PIs comprising Thomas Edwards, Adam Nelson, Stuart Warriner and Andrew Wilson (Leeds University, Astbury Centre) and Alex Breeze (AstraZeneca), the team recently published their first paper resulting from this project, see also feature in online magazine Chemistry Views.
The transcription factor, hypoxia inducible factor (HIF), plays a central role in the cellular response to hypoxic conditions; HIF-1α is stabilised and translocated to the nucleus, where it forms heterodimers and recruits transcriptional co-activator proteins such as p300. The resultant expression of proteins promotes the development of new vasculature and hence represents a means to resupply tumours with oxygen, hence this PPI is a potential target for the development of anticancer therapeutics. In their first publication resulting from the collaborative project, oligoamide helix mimetics were developed that exhibit low μM and selective inhibition of the HIF-1α/p300 interaction (Fig 1) – these small molecules were the first biophysically characterised HIF-1α/p300 PPI inhibitors and the first examples of small-molecule aromatic oligoamide helix mimetics to be shown to have a selective binding profile.