α-Helix mimetics as inhibitors of protein–protein interactions

The inhibition of protein–protein interactions using small molecules is a viable approach for the treatment of a range of pathological conditions that result from a malfunctioning of these interactions. Our strategy for the design of such agents involves the mimicry of side-chain residues on one face of the α-helix; these residues frequently play a key role in mediating protein–protein interactions. The first-generation terphenyl scaffold, with a 3,2′,2″-substitution pattern, is able to successfully mimic key helix residues and disrupt therapeutically relevant interactions, including the Bcl-X_L–Bak and the p53–hDM2 (human double minute 2) interactions that are implicated in cancer. The second- and third-generation scaffolds have resulted in greater synthetic accessibility and more drug-like character in these molecules.