The rational design of low-molecular weight ligands that disrupt protein−protein interactions is still a challenging goal in medicinal chemistry. Our approach to this problem involves the design of molecular scaffolds that mimic the surface functionality projected along one face of an α-helix. Using a terphenyl scaffold, which in a staggered conformation closely reproduces the projection of functionality on the surface of an α-helix, we designed mimics of the pro-apoptotic α-helical Bak-peptide as inhibitors of the Bak/Bcl-x_L interaction. This led to the development of a potent Bcl-x_L antagonist (K_D = 114 nM), whose binding affinity for Bcl-x_L was assessed by a fluorescence polarization assay. To determine the binding site of the developed inhibitor we used docking studies and an HSQC-NMR experiment with ¹⁵N-labeled Bcl-x_L protein. These studies suggest that the inhibitor is binding in the same hydrophobic cleft as the Bak- and Bad-peptides.