Small-Molecule Proteomimetic Inhibitors of the HIF-1α-p300 Protein-Protein Interaction

The therapeutically relevant hypoxia inducible factor HIF-1 alpha-p300 protein-protein interaction can be orthosterically inhibited with alpha-helix mimetics based on an oligoamide scaffold that recapitulates essential features of the C-terminal helix of the HIF-1 alpha C-TAD (C-terminal transactivation domain). Preliminary SAR studies demonstrated the important role of side-chain size and hydrophobicity/hydrophilicity in determining potency. These small molecules represent the first biophysically characterised HIF-1 alpha-p300 PPI inhibitors and the first examples of small-molecule aromatic oligoamide helix mimetics to be shown to have a selective binding profile. Although the compounds were less potent than HIF-1 alpha, the result is still remarkable in that the mimetic reproduces only three residues from the 42-residue HIF-1 alpha C-TAD from which it is derived.