Design, synthesis and biological evaluation of novel 4,5-dihydro-[1,2,4] triazolo[4,3-f] pteridine derivatives as potential BRD4 inhibitors

被引：15

作者：

Bi, Xinzhou ^{[1
]}

Li, Jieming ^{[1
]}

Li, Jiuhui ^{[1
]}

Shi, Wei ^{[1
]}

Dai, Yuxuan ^{[1
]}

Li, Qifei ^{[1
]}

Zhang, Wenjie ^{[1
]}

Huang, Wenlong ^{[1
,2
]}

Qian, Hai ^{[1
,2
]}

Jiang, Cheng ^{[3
,4
]}

机构：

[1] China Pharmaceut Univ, Ctr Drug Discovery, State Key Lab Nat Med, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China

[2] China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China

[3] China Pharmaceut Univ, Jiangsu Key Lab Drug Design & Optimizat, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China

[4] China Pharmaceut Univ, Key Lab Prot Chem & Struct Biol, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2019年 / 27卷 / 13期

基金：

美国国家科学基金会;

关键词：

BRD4; inhibitors; Anti-tumor; BI-2536; c-Myc; BET INHIBITORS; DRUG DISCOVERY; BROMODOMAIN; 2-THIAZOLIDINONES;

D O I：

10.1016/j.bmc.2019.05.006

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Recently, diverse kinase inhibitors were reported having interaction with BRD4. It provided a strategy for developing a new structural framework for the next-generation BRD4-selective inhibitors. Starting from PLK1 kinase inhibitor BI-2536, we designed 18 compounds by modifying dihydropteridine core. Compound 23 showed potent BRD4 inhibitory activities with IC50 of 79 nM and no inhibitory activities for PLK1. Cell antiproliferation assay was performed and potent inhibitory activity against MV4; 11 with IC50 of 1.53 mu M. Cell apoptosis and western blotting indicated compound 23 induced apoptosis by down-regulating c-Myc. These novel selective BRD4 inhibitors provided new lead compounds for further drug development.

引用

页码：2813 / 2821

页数：9

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