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J Med Chem. 2010 May 13;53(9):3465-79. doi: 10.1021/jm901004c.

Design, synthesis, and interaction study of quinazoline-2(1H)-thione derivatives as novel potential Bcl-xL inhibitors.

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Department of Molecular Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.


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-x(L), 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-x(L) 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-x(L), 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.

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