A wide range of small molecule scaffolds capable of mimicking protein α-helices to modulate protein-protein interactions have been reported, yet their target selectivity is poorly understood. Here, we report the changes to the whole protoeme of SJSA-1 osteosarcoma cells following treatment with three structurally distinct classes of α-helix mimetics, N-substituted oligobenzamides, pyrrolopyrimidines, and oxopiperazines, all reported to inhibit the interaction between the tumour suppressor protein p53 and its negative regulator murine double minute 2 (MDM2).