Design, Synthesis and Interaction Study of Quinazoline-2(1H)-Thione Derivatives as Novel Bcl-xL Inhibitors

Yu Feng, Xiao Ding, Tao Chen, Lili Chen , Fang Liu, Xu Jia, Xiaomin Luo,Xu Shen, Kaixian Chen, Hualiang Jiang, Hui Wang, Hong Liu, Dongxiang Liu

Development of inhibitors to antagonize the activities of antiapoptotic Bcl-2 family proteins is of
particular interest in cancer chemotherapy. We discovered a quinazoline-2(1H)-thione derivative
(DCBL55) as a new Bcl-xL, Bcl-2, and Mcl-1 inhibitor by virtual database screening. We systematically
modified the structure of compound 1 by chemical synthesis. The interactions of the compounds with
Bcl-xL were predicted by molecular modeling simulations, which were confirmed by structure-activity
relationship analysis and protein mutation studies. Three locations at the hydrophobic groove of Bcl-xL,
referred to as P2, P4, and P5, were found to contribute to the ligand interactions. Although the
compounds induced mitochondrial potential reduction, caspase activation, and ROS generation, the
cytotoxicities and the ultrastructural changes of outer mitochondrial membrane suggested that the
compounds may target additional proteins outside the Bcl-2 family. Altogether, the present study
provides new lead compounds and critical structural information for further development of more
potent and specific inhibitors of antiapoptotic Bcl-2 family proteins.