通过基于结构的设计和结构活性关系分析发现选择性 Mcl-1 抑制剂。
Discovery of selective Mcl-1 inhibitors via structure-based design and structure-activity relationship analysis.
机构信息
State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China.
School of Life Science and Technology, Dalian University of Technology, Dalian, China.
出版信息
Biochem Biophys Res Commun. 2019 May 14;512(4):921-926. doi: 10.1016/j.bbrc.2019.03.102. Epub 2019 Mar 28.
Based on Nap-1, a Mcl-1/Bcl-2 dual inhibitor reported by our group, we carried out a structure-guided molecular design and structure-activity relationship (SAR) analysis to study structural features contributing to Mcl-1 binding selectivity and affinity. A series of derivatives of Nap-1 with various pharmacophores were synthesized and among them a dual Mcl-1/Bcl-2 inhibitor A4 with enhanced affinities (IC = 0.15 μM for Mcl-1, 0.43 μM for Bcl-2) and a selective Mcl-1 inhibitor B9 with a 20-fold selectivity over Bcl-2 (IC = 0.51 μM vs 9.46 μM) were obtained by enzyme linked immunosorbent assay (ELISA). The SAR data and binding modes of A4 and B9 investigated by 2D-NMR derived docking study illustrated that p2 pockets exhibiting different geometry and binding features between Mcl-1 and Bcl-2 contribute to specific binding properties of Mcl-1. In addition, apoptosis-inducing potencies of A4 and B9 were consistent with their binding selectivity determined in vitro.
基于我们小组报道的 Nap-1（一种 Mcl-1/Bcl-2 双重抑制剂），我们进行了结构导向的分子设计和构效关系（SAR）分析，以研究对 Mcl-1 结合选择性和亲和力有贡献的结构特征。我们合成了一系列具有不同药效团的 Nap-1 衍生物，其中双 Mcl-1/Bcl-2 抑制剂 A4 的亲和力增强（对 Mcl-1 的 IC = 0.15 μM，对 Bcl-2 的 IC = 0.43 μM），对 Bcl-2 的选择性提高了 20 倍（IC = 0.51 μM 对 9.46 μM），通过酶联免疫吸附测定（ELISA）获得。通过二维 NMR 衍生对接研究的 SAR 数据和 A4 和 B9 的结合模式表明，p2 口袋在 Mcl-1 和 Bcl-2 之间表现出不同的几何形状和结合特征，这有助于 Mcl-1 的特异性结合特性。此外，A4 和 B9 的诱导凋亡能力与其在体外确定的结合选择性一致。
Zotero 插件