Topologically Tunable α‐Helix Mimetics for Targeting Protein–Protein Interactions

A novel strategy to replicate diverse α-helical conformations found at the interfaces of protein-protein interactions is developed with a topologically tunable biphenyl scaffold. A set of N,N'-diphenyl-4,4'-biphenyldicarboxamide scaffolds were designed as customizable α-helix mimetics, capable of reproducing a wide range of helical surfaces that may be difficult to be replicated with previously reported α-helix mimetics. These scaffolds were evaluated for their capability to mimic the α-helical BH3 domains of Bcl-2 family proteins. By modifying the substituents and their positions, both pan-active and selective inhibitors of anti-apoptotic Bcl-2 family members were developed, each exhibiting distinct binding profiles. This unique approach offers a powerful tool for mimicking naturally occurring α-helices and distinguishing subtle differences in bound conformations with target proteins.