Discovery and structure-activity relationship studies of N-substituted indole derivatives as novel Mcl-1 inhibitors.
Discovery and structure-activity relationship studies of N-substituted indole derivatives as novel Mcl-1 inhibitors.
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DOI：
10.1016/j.bmcl.2017.03.028
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发表时间：
2017-05
影响因子：
2.7
通讯作者：
Shenglin Luan;Qi Ge;Yedong Chen;Mingyang Dai;Jinyu Yang;Kun Li;Dan Liu;Linxiang Zhao
中科院分区：
文献类型：
--
作者：
Shenglin Luan;Qi Ge;Yedong Chen;Mingyang Dai;Jinyu Yang;Kun Li;Dan Liu;Linxiang Zhao
髓系细胞白血病-1(Mcl-1)是一种重要的抗凋亡蛋白，通过蛋白质间相互作用发挥作用。我们discoveredLSL-A6(2-((2-carbamoyl-1-(3-(4-methoxyphenoxy)propyl)-1H-indol-6-yl)oxy)acetic酸)与一种新型的N-取代吲哚支架干扰Mcl-1的结合，作为一种新型的Mcl-1抑制剂。分子模拟表明，该化合物通过与P2和R263热点相互作用与Mcl-1结合。对吲哚核、疏水尾和酸性链等几个基团进行了结构修饰，并分析了构效关系。经Hit-to-Lead修饰后，获得了干扰Mcl-1结合的最有效化合物24d，其Ki值为110nM。
Myeloid cell leukemia-1 (Mcl-1) is an important antiapoptotic protein functioning through protein-protein interactions. We discoveredLSL-A6(2-((2-carbamoyl-1-(3-(4-methoxyphenoxy)propyl)-1H-indol-6-yl)oxy)acetic acid) with a novelN-substituted indole scaffold to interfere Mcl-1 binding as a novel Mcl-1 inhibitor. Molecular modeling indicated that this compound binds with Mcl-1 by interaction with P2 and R263 hot-spots. Structure modification focused on several moieties including indole core, hydrophobic tail and acidic chain were conducted and structure-activity relationship was analyzed. The most potent compound24dwhich exhibitedKivalue of 110 nM for interfering Mcl-1 binding was obtained after hit-to-lead modification.