title: Design, synthesis, and interaction study of quinazoline-2(1H)-thione derivatives as novel potential Bcl-xL inhibitors.
abstract: 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.
authors.affiliation: Department of Molecular Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Feng
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Xu
authors.initials: X
authors.lastname: Jia
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Dongxiang
authors.initials: D
authors.lastname: Liu
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000187:drug effects; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D051336:Mitochondrial Membranes; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D011799:Quinazolines; D051020:bcl-X Protein