4.4 Article

α-Helix mimetics as inhibitors of protein-protein interactions

Journal

BIOCHEMICAL SOCIETY TRANSACTIONS
Volume 36, Issue -, Pages 1414-1417

Publisher

PORTLAND PRESS LTD
DOI: 10.1042/BST0361414

Keywords

helix mimetic; inhibitor; medicinal chemistry; protein-protein interaction; rational design

Funding

  1. National Institutes of Health [GM69850]

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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 a-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 BCI-X-L-Bak and the pS3-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.

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