Novel phenanthridin-6(5H)-one derivatives as potent and selective BET bromodomain inhibitors: Rational design, synthesis and biological evaluation

被引：9

作者：

Zhi, Yanle ^{[1
]}

Wang, Shu ^{[2
]}

Huang, Wenhai ^{[2
]}

Zeng, Shenxin ^{[2
]}

Liang, Meihao ^{[2
]}

Zhang, Chixiao ^{[2
]}

Ma, Zhen ^{[2
]}

Wang, Zunyuan ^{[2
]}

Zhang, Zhimin ^{[2
]}

Shen, Zhengrong ^{[2
]}

机构：

[1] Henan Univ Tradit Chinese Med, Coll Pharm, Zhengzhou 450046, Henan, Peoples R China

[2] Zhejiang Acad Med Sci, Inst Mat Med, Key Lab Neuropsychiat Drug Res Zhejiang Prov, Hangzhou 310013, Zhejiang, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 179卷

关键词：

Rational drug design; BET bromodomain inhibitor; Antiproliferative effect; Apoptosis; Pharmacokinetics; TRANSCRIPTION ELONGATION; P-TEFB; DISCOVERY; SERIES; IDENTIFICATION; OPTIMIZATION; RECRUITMENT; STRATEGY; CANCER;

D O I：

10.1016/j.ejmech.2019.06.067

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of BET family of bromodomain is an appealing intervention strategy for several cancers and inflammatory diseases. This article highlights our work toward the identification of potent, selective, and efficacious BET inhibitors using a structure-based approach focused on improving potency. Our medicinal chemistry efforts led to the identification of compound 24, a novel phenanthridin-6(5H)-one derivative, as a potent (IC50 = 0.24 mu M) and selective BET inhibitor with excellent cancer cell lines inhibitory activities and favorable oral pharmacokinetic properties. (C) 2019 Elsevier Masson SAS. All rights reserved.

引用

页码：502 / 514

页数：13

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