Design, synthesis, and characterization of a potent, nonpeptide, cell-permeable, bivalent smac mimetic that concurrently targets both the BIR2 and BIR3 domains in XIAP
Design, synthesis, and characterization of a potent, nonpeptide, cell-permeable, bivalent smac mimetic that concurrently targets both the BIR2 and BIR3 domains in XIAP
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DOI：
10.1021/ja074725f
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发表时间：
2007-12-12
影响因子：
15
通讯作者：
Wang, Shaomeng
中科院分区：
文献类型：
--
作者：
Sun, Haiying;Nikolovska-Coleska, Zaneta;Wang, Shaomeng
XIAP是一种中枢细胞凋亡调节剂，通过其BIR2和BIR3结构域分别结合和抑制效应体caspase-3/-7和启动体caspase-9，从而抑制细胞凋亡。二聚体形式的Smac蛋白通过同时靶向XIAP的BIR2和BIR3结构域，有效地拮抗XIAP。我们报道了一种非肽、细胞渗透性、二价小分子（SM-164）的设计、合成和表征，它模仿Smac蛋白靶向XIAP。我们的研究表明，SM-164与含有两个BIR结构域的XIAP结合，IC50值为1.39 nM，分别是其单价对应物和天然Smac AVPI肽的300倍和7000倍。SM-164同时与XIAP中的两个BIR结构域相互作用，并在无细胞功能和基于细胞的检测中作为XIAP的超强拮抗剂。SM-164靶向细胞XIAP，在HL-60白血病细胞系中，浓度低至1 nM即可有效诱导细胞凋亡。二价SM-164在结合、功能和细胞分析中的效力比其相应的单价Smac模拟物高2-3个数量级。
XIAP is a central apoptosis regulator that inhibits apoptosis by binding to and inhibiting the effectors caspase-3/-7 and an initiator caspase-9 through its BIR2 and BIR3 domains, respectively. Smac protein in its dimeric form effectively antagonizes XIAP by concurrently, targeting both its BIR2 and BIR3 domains. We report the design, synthesis, and characterization of a nonpeptide, cell-permeable, bivalent small-molecule (SM-164) which mimics Smac protein for targeting XIAP. Our study shows that SM-164 binds to XIAP containing both BIR domains with an IC50 value of 1.39 nM, being 300 and 7000 times more potent than its monovalent counterparts and the natural Smac AVPI peptide, respectively. SM-164 concurrently interacts with both BIR domains in XIAP and functions as an ultrapotent antagonist of XIAP in both cell-free functional and cell-based assays. SM-164 targets cellular XIAP and effectively induces apoptosis at concentrations as low as 1 nM in the HL-60 leukemia cell line. The potency of bivalent SM-164 in binding, functional, and cellular assays is 2-3 orders of magnitude higher than its corresponding monovalent Smac mimetics.