Structure-based design, synthesis, and evaluation of Bcl-2/Mcl-1 dual inhibitors
Structure-based design, synthesis, and evaluation of Bcl-2/Mcl-1 dual inhibitors
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Bcl-2/Mcl-1 双抑制剂的基于结构的设计、合成和评估
DOI：
10.1002/ardp.202000005
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发表时间：
2020
影响因子：
5.1
通讯作者：
Zhang Zhichao
中科院分区：
文献类型：
--
作者：
Zhu Junjie;Wang Ziqian;Guo Zongwei;Zhang Xiaodong;Song Ting;Guo Yafei;Ji Tong;Zhang Zhichao
Based on our previously reported Bcl‐2/Mcl‐1 dual inhibitor 4‐thiomorpholinyl‐2‐cyano‐3‐amidinophenalenone (A1) that simultaneously occupies the p2 and p4 hydrophobic pockets of Bcl‐2 and Mcl‐1, we optimized molecules with different bond angles of the groups extending to the p4 pocket and bulky hydrophobic groups to explore p2. Research on structure–activity relationship resulted in a new derivativeB4that is capable of occupying both the p2 and p4 more deeply and completely thanA1, withKivalues determined by fluorescence polarization assay (FPAs) improving to 0.31 μM for Bcl‐2 and 0.16 μM for Mcl‐1. Furthermore,B4exhibited selective lethality on cancer cells over normal cells. It showed stronger apoptosis induction than (–)‐gossypol on a Bcl‐2/Mcl‐1‐dependent cancer cell line and killed an Mcl‐1‐dependent cell line which is resistant to ABT‐199 treatment.
