State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian 116012, People's Republic of China.
Eur J Med Chem. 2011 Sep;46(9):3909-16. doi: 10.1016/j.ejmech.2011.05.062. Epub 2011 May 31.
Based on our previous discovery of a dual inhibitor of Mcl-1 and Bcl-2, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (1, S1), and guided by structure insight of 1 complex with Mcl-1 and Bcl-2, we exploited the spatial orientation of BH3 groove of the two proteins by a series of analogues of 1. These analogues contain substitutes with various steric hindrance designed to explore the width and length of the p2 pocket. The structure-activity relationships (SARs) studies together with docking studies and cell-based assays proved that the p2 pocket of Mcl-1 is relatively wider and shorter than that of Bcl-2. A novel dual inhibitor 6 was obtained based on these new findings that it exhibited nanomalar affinities toward Mcl-1 and Bcl-2, as well as nanomalar cytotoxicity activity against multiple cancer cell lines.
基于我们之前发现的 Mcl-1 和 Bcl-2 的双重抑制剂 3-硫代吗啉-8-氧代-8H-吖萘并[1,2-b]吡啶-9-甲腈（1，S1），并通过 1 与 Mcl-1 和 Bcl-2 的复合物的结构洞察力，我们利用了这两种蛋白质的 BH3 槽的空间方向，通过一系列 1 的类似物。这些类似物包含各种空间位阻的取代基，旨在探索 p2 口袋的宽度和长度。构效关系（SAR）研究以及对接研究和基于细胞的测定证明，Mcl-1 的 p2 口袋相对于 Bcl-2 更宽且更短。根据这些新发现，获得了一种新型双重抑制剂 6，它对 Mcl-1 和 Bcl-2 表现出纳摩尔亲和力，并且对多种癌细胞系具有纳摩尔细胞毒性活性。
