Protein-protein interactions (PPIs) are implicated in virtually all biological pathways and are emerging as new potential targets for therapeutic intervention. [1] Of particular interest are α-helix mediated PPIs where a helical region of protein, the helix donor, binds into a cleft on a partner protein, the helix acceptor. [2] This region of interaction has the well-defined structure of an α-helix and can therefore be inhibited by small molecules that bind tightly into the helix acceptor cleft. One example of a helix donor is Hypoxia Inducible Factor (HIF)-1α which forms a key PPI with the protein p300 leading to the hypoxic response cascade. [3] Tumours rapidly deplete the oxygen supply to the tissue and cancerous cells exploit the hypoxic response pathway to resupply the tumour with oxygen. Inhibition of the HIF-1α/p300 interaction is therefore of interest in the development of new treatments for cancer. [4]
We report a biophysical investigation into the interaction of the two binding partners, leading to the development of a biophysical assay capable of identifying inhibitors. This has allowed us to identify a series of low µM inhibitors using rational structure based design. [5] These compounds are the first biophysically characterised small molecule HIF-1α/p300 inhibitors and are selective over other therapeutically relevant PPIs.

1 C. W. Bertoncini, A. Higueruelo and X. Salvatella in Protein Surface Recognition: Approaches for Drug Discovery, ed. E. Giralt, M.W. Peczuh and X. Salvatella, Wiley, New York, 1st edn., 2010
2 T.A. Edwards and A.J. Wilson, Amino Acids, 2011, 41, 743
3 S.J. Freedman, Z-Y. J. Sun, F. Poy, A.L. Kung, D.M. Livingston, G. Wagner and M.J. Eck, Proc.Natl.Acad.Sci.U.S.A. 2002, 8, 5367
4 I.N. Nordgren and A. Tavassoli, Chem.Soc.Rev. 2011, 40, 4307
5 G.M. Burslem, H.F. Kyle, A.L. Breeze, T.A. Edwards, A. Nelson, S.L. Warriner, A.J. Wilson, ChemBioChem, 2014, DOI:10.1002/cbic.201400009