Discovery of selective Mcl-1 inhibitors via structure-based design and structure-activity relationship analysis
Discovery of selective Mcl-1 inhibitors via structure-based design and structure-activity relationship analysis
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通过基于结构的设计和构效关系分析发现选择性 Mcl-1 抑制剂
DOI：
10.1016/j.bbrc.2019.03.102
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发表时间：
2019-05-14
影响因子：
3.1
通讯作者：
Zhang, Zhichao
中科院分区：
文献类型：
--
作者：
He, Nianzhe;Liu, Peng;Zhang, Zhichao
基于本课组报道的Mcl-1/Bcl-2双抑制剂Nap-1，我们进行了结构导向的分子设计和构效关系（SAR）分析，研究了影响Mcl-1结合选择性和亲和力的结构特征。合成了一系列具有不同药效团的Nap-1衍生物，并通过酶联免疫吸附试验（ELISA）获得了Mcl-1/Bcl-2双抑制剂A4 （Mcl(-1) IC50 = 0.15 μ M, Bcl-2 IC50 = 0.43 μ M）和Mcl-1选择性抑制剂B9 (IC50 = 0.51 μ M vs 9.46 μ M)，比Bcl-2选择性高20倍。2D-NMR衍生对接研究对A4和B9的SAR数据和结合模式进行了研究，结果表明，在Mcl-1和Bcl-2之间具有不同几何形状和结合特征的p2口袋有助于Mcl-1的特异性结合特性。此外，A4和B9的诱导凋亡能力与其体外测定的结合选择性一致。(C) 2019 Elsevier Inc.版权所有。
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 (IC50 = 0.15 mu M for Mcl(-1), 0.43 mu M for Bcl-2) and a selective Mcl-1 inhibitor B9 with a 20-fold selectivity over Bcl-2 (IC50 = 0.51 mu M vs 9.46 mu M) 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. (C) 2019 Elsevier Inc. All rights reserved.