Bcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like α-Helical Mimetics
Bcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like α-Helical Mimetics
复制标题
基于通用类金字塔 α 螺旋模拟物的 Bcl-2/MDM2 双抑制剂
DOI：
10.1021/acs.jmedchem.5b01913
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发表时间：
2016-04-14
影响因子：
7.3
通讯作者：
Zhang, Zhichao
中科院分区：
文献类型：
--
作者：
Wang, Ziqian;Song, Ting;Zhang, Zhichao
由于α-螺旋在其结合界面处的螺旋度不同，没有合理设计表现出Bd-2/MDM 2双重抑制的α-螺旋模拟物。在此，我们从邻苯折叠体中提取了一个单转角α-螺旋模拟邻三芳烃单元。我们用可旋转的C-N键连接苯甲酰胺底物，构建了一种新的半刚性的类β-螺旋支架，该支架可以支持其两个转角的α-螺旋模拟，而没有芳香堆积相互作用，并且可以采用p53和BH 3-only肽的关键残基的不同二面角。在此基础上，我们设计了一系列的取代基，以捕获p53和BimBH 3的关键残基，并平衡它们之间的体积差异。通过FP、ITC和NMR光谱鉴定，获得了以平衡的亚微摩尔亲和力直接结合Mcl-1、Bcl-2和MDM 2的化合物6 e（zq-1）。细胞实验表明其具有同时抑制Bcl-2/MDM 2的抗肿瘤作用。
No alpha-helical mimetic that exhibits Bd-2/MDM2 dual inhibition has been rationally designed due to the different helicities of the alpha-helixes at their binding interfaces. Herein, we extracted a one-turn alpha-helix-mimicking ortho-triarene unit from o-phenylene foldamers. Linking benzamide substrates with a rotatable C-N bond, we constructed a novel semirigid pyramid-like scaffold that could support its two-turn alpha-helix mimicry without aromatic stacking interactions and could adopt the different dihedral angles of the key residues of p53 and BH3-only peptides. On the basis of this universal scaffold, a series of substituent groups were installed to capture the key residues of both p53TAD and BimBH3 and balance the differences of the bulks between them. Identified by FP, ITC, and NMR spectroscopy, a compound 6e (zq-1) that directly binds to Mcl-1, Bcl-2, and MDM2 with balanced submicromolar affinities was obtained. Cell-based experiments demonstrated its antitumor ability through Bcl-2/MDM2 dual inhibition simultaneously.