Terephthalamide derivatives as mimetics of helical peptides: Disruption of the Bcl-x_L/Bak interaction

A series of Bcl-x_L/Bak antagonists, based on a terephthalamide scaffold, was designed to mimic the α-helical region of the Bak peptide. These molecules showed favorable in vitro activities in disrupting the Bcl-x_L/Bak BH3 domain complex (terephthalamides 9 and 26, K _i = 0.78 ± 0.07 and 1.85 ± 0.32 μM, respectively). Extensive structure-affinity studies demonstrated a correlation between the ability of terephthalamide derivatives to disrupt Bcl-x_L/Bak complex formation and the size of variable side chains on these molecules. Treatment of human HEK293 cells with the terephthalamide derivative 26 resulted in disruption of the Bcl-x_L/Bax interaction in whole cells with an IC₅₀ of 35.0 μM. Computational docking simulations and NMR experiments suggested that the binding cleft for the BH3 domain of the Bak peptide on the surface of Bcl-x_L is the target area for these synthetic inhibitors.