alpha-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 alpha-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.
Saraogi
Ishu
I
Department of Chemistry, Yale University, New Haven, CT 06520, USA.
Hamilton
Andrew D
AD
D000818:Animals; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects*; D013730:Terphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*
D013730:Terphenyl Compounds