Novel soluble myeloid cell leukemia sequence 1 (Mcl-1) inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g) developed using a fragment-based approach.
Novel soluble myeloid cell leukemia sequence 1 (Mcl-1) inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g) developed using a fragment-based approach.
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DOI：
10.1016/j.ejmech.2012.10.050
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发表时间：
2013
影响因子：
6.7
通讯作者：
Zhichao Zhang;T. Song;Xiangqian Li;Zhiyong Wu;Yingang Feng;Feibo Xie;Chengwu Liu;Jianquan Qin;Hongbo Chen
中科院分区：
文献类型：
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作者：
Zhichao Zhang;T. Song;Xiangqian Li;Zhiyong Wu;Yingang Feng;Feibo Xie;Chengwu Liu;Jianquan Qin;Hongbo Chen
基于已知的纳摩尔Bcl-2同源结构域3（BH 3）模拟物3-硫代吗啉-8-氧代-8H-苊并[1，2-B]吡咯-9-甲腈（S1，MW：331），我们应用基于片段的方法获得在水-乙醇（9：1）共溶剂中具有改善的亲和力和改善的溶解度的BH 3模拟物。在解构1（S1）之后，我们得到片段氰基乙酰胺（4），其被确定为配体效率（LE）热部分。通过从片段4开始的片段进化进行合理优化后，获得了与1相比亲和力增加6倍的较小Mcl-1抑制剂（E，E）-2-（苄基氨基羰基）-3-苯乙烯基丙烯腈（4g，MW：288），如我们的优化曲线所预测的，并通过Mcl-1蛋白质核磁共振（NMR）鉴定。
Based on a known nanomolar Bcl-2 homology domain 3 (BH3) mimetic 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b] pyrrole-9-carbonitrile (S1, MW: 331), we applied a fragment-based approach to obtain BH3 mimetics with improved affinity and improved solubility in a water–ethanol (9:1) cosolvent. After the deconstruction of 1 (S1), we obtained fragment cyanoacetamide (4), which was determined to be a ligand efficiency (LE) hot part. After a rational optimization through fragment evolution beginning with fragment 4, a smaller Mcl-1 inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g, MW: 288) with a 6-fold increase in affinity compared to 1 was obtained, as predicted by our optimization curve and identified by Mcl-1 protein nuclear magnetic resonance (NMR).