Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization
Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization
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DOI：
10.1016/j.bmc.2012.09.041
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发表时间：
2012-11-15
影响因子：
3.5
通讯作者：
Seneci, Pierfausto
中科院分区：
文献类型：
--
作者：
Lecis, Daniele;Mastrangelo, Eloise;Seneci, Pierfausto
对通过头-头（8）、尾-尾（9）或头-尾接头（10）连接的新型促凋亡、同二聚体和异二聚体Smac模拟物/IAP抑制剂进行生物学和结构表征。体外表征（与来自XIAP和cIAP 1的BIR 3和接头-BIR 2-BIR 3结构域的结合，细胞毒性测定）鉴定了来自每个二聚体家族的早期先导物。计算模型和结构研究（结晶学，NMR，凝胶过滤）部分合理化观察到的每个二聚体类的属性。尾-尾二聚体9a在乳腺和卵巢肿瘤模型中显示出活性，突出了基于N-AVPI样4-取代的1-氮杂-2-氧代-双环[5.3.0]癸烷支架的二聚体Smac模拟物/IAP抑制剂作为潜在的抑制剂的潜力。(C)2012爱思唯尔有限公司版权所有。
Novel pro-apoptotic, homodimeric and heterodimeric Smac mimetics/IAPs inhibitors connected through head-head (8), tail-tail (9) or head-tail linkers (10), were biologically and structurally characterized. In vitro characterization (binding to BIR3 and linker-BIR2-BIR3 domains from XIAP and cIAP1, cytotoxicity assays) identified early leads from each dimer family. Computational models and structural studies (crystallography, NMR, gel filtration) partially rationalized the observed properties for each dimer class. Tail-tail dimer 9a was shown to be active in a breast and in an ovary tumor model, highlighting the potential of dimeric Smac mimetics/IAP inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxo-bicyclo[5.3.0]decane scaffold as potential antineoplastic agents. (C) 2012 Elsevier Ltd. All rights reserved.