Design, synthesis, and activity evaluation of broad-spectrum small-molecule inhibitors of anti-apoptofic Bcl-2 family proteins: Characteristics of broad-spectrum protein binding and its effects on anti-tumor activity

摘要

On the basis of the comparison of the structure of the Bim BH3:Bcl-(x)(t) complex and that of the ABT-737:Bcl-(x)(L) complex,a series of class A compounds were designed.These compounds had the basic skeleton of ABT-737 and the h2 residues of Bim BH3.These residues had shown themselves to he relevant to Bim BH3's broad-spectrum binding properties in saturation mutagenesis assays.Unlike ABT-737,which is a selective inhibitor of anti-apoptotic members of the Bcl-2 protein family,the class A compounds showed broad-spectrum binding activity to target proteins similar to those of Bim BH3 peptide.Then class B compounds were synthesized by modifying the structure of the most effective dass A compound,A-4.Most of these class B compounds showed better binding affinity to the target proteins than the class A compounds bad.They also showed themselves more effective than ABT-737 at inhibiting growth in multiple tumor cell lines known to express Bcl-(x)(L).Bcl-2,and Mcl-1 proteins at high levels.Compounds B-11 and B-12 had the strongest anti-tumor activity of any compounds we produced.This study suggests that it is feasible to design small-molecule inhibitors based on the structure of Bim BH3,which shows broad-spectrum binding to Bcl-(x)(L) Bcl-2.and Mcl-1 proteins.Our results also suggest that the broad-spectrum properties of small-molecule inhibitors binding to target proteins play a critical role in inhibiting the growth of many tumor cells.Finally.our study provides a series of lead compounds that merit further research into anti-cancer therapeutics.