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Structure‐based design, synthesis, and evaluation of Bcl‐2/Mcl‐1 dual inhibitors
Author(s) -
Zhu Junjie,
Wang Ziqian,
Guo Zongwei,
Zhang Xiaodong,
Song Ting,
Guo Yafei,
Ji Tong,
Zhang Zhichao
Publication year - 2020
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.202000005
Subject(s) - chemistry , cell culture , molecule , apoptosis , stereochemistry , derivative (finance) , biochemistry , biology , genetics , organic chemistry , financial economics , economics
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 derivative B4 that is capable of occupying both the p2 and p4 more deeply and completely than A1 , with K i values determined by fluorescence polarization assay (FPAs) improving to 0.31 μM for Bcl‐2 and 0.16 μM for Mcl‐1. Furthermore, B4 exhibited 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.