title: Design, synthesis, and activity evaluation of selective inhibitors of anti-apoptotic Bcl-2 proteins: The effects on the selectivity of the P1 pockets in the active sites.
abstract: The anti-apoptotic Bcl-2 proteins are attractive targets for anti-cancer drug development, and the discovery of their selective inhibitors has become a research focus. In this Letter, obvious differences in the P1 pocket of the active site between Bcl-2, Bcl-xL, and Mcl-1 proteins were proposed by the structural comparison of these proteins. As a result, the groups in their inhibitors binding to the P1 pockets may have significant effect on the selectivity for these proteins. Based on this hypothesis, five types of derivatives of the lead compound B-1 were designed, and several highly selective inhibitors of Bcl-xL(E-1) or Mcl-1 proteins (G) were found. The selective inhibitors of Mcl-1 protein found in this Letter provide new structural types for the development of novel antitumor agents.
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Mingping
authors.initials: M
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tian
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Chongqing
authors.initials: C
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Shihai
authors.initials: S
authors.lastname: Lu
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.affiliation: Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Song
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Youjun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: zhuju@smmu.edu.cn.
authors.forename: Ju
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: zhiyuli@cpu.edu.cn.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: canhuizheng@smmu.edu.cn.
authors.forename: Canhui
authors.initials: C
authors.lastname: Zheng
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2
keywords: Anti-apoptotic Bcl-2 proteins; Anti-tumor; Mcl-1 protein; Selective inhibitors