The discovery of new Bcl-2 protein-protein interaction antagonists is described. We replaced the northern fragment of ABT737 (π-π stacking interactions) with structurally simplified hydrophobic cage structures with much reduced conformational flexibility and rotational freedom. The binding mode of the compounds was elucidated by X-ray crystallography, and the compounds showed excellent oral bioavailability and clearance in rat PK studies.
Keywords: Bcl-2 inhibitors; bioisoteres; cancer therapeutics; protein−protein interaction; π−π stacking interactions; π−π stacking isosteres.