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-XL–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.
Conference Article| November 19 2008
α-Helix mimetics as inhibitors of protein–protein interactions
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Ishu Saraogi, Andrew D. Hamilton; α-Helix mimetics as inhibitors of protein–protein interactions. Biochem Soc Trans 1 December 2008; 36 (6): 1414–1417. doi: https://doi.org/10.1042/BST0361414
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