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

Abstract 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.