The design of a cross-acridine scaffold mimicking the i, i+3, i+5, and i+7 residues distributed over a two-face, two-turn alpha-helix is described. Docking studies and 2D H-1, N-15 HSQC NMR spectroscopy provide compelling evidence that compound 3d accurately reproduces the arrangement of four hotspots in the Bim BH3 peptide to permit binding to the Mcl-1 and Bcl-2 proteins (K-i 0.079 and 0.056 mu m, respectively). Furthermore, the hotspot mutation could also be mimicked by individual or multiple deletions of side chains on the scaffold.