Design, synthesis and biological evaluation of 7-methylimidazo[1,5-a] pyrazin-8(7H)-one derivatives as BRD4 inhibitors

被引：13

作者：

Zhao, Leilei ^{[1
]}

Yang, Yifei ^{[2
]}

Guo, Yahui ^{[1
]}

Yang, Lingyun ^{[1
]}

Zhang, Jian ^{[1
]}

Zhou, Jinpei ^{[2
]}

Zhang, Huibin ^{[1
]}

机构：

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

[2] China Pharmaceut Univ, Dept Med Chem, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2017年 / 25卷 / 08期

关键词：

BRD4; Bromodomain; Lysine acetylation; Antitumor; BET BROMODOMAIN INHIBITORS; SMALL-MOLECULE INHIBITORS; ACUTE-LEUKEMIA; C-MYC; DISCOVERY; POTENT; CANCER; OTX015;

D O I：

10.1016/j.bmc.2017.03.008

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：

BRD4 is an attractive target for antitumor due to its important role in regulation of gene transcription. In this paper, we synthesized a series of 7-methylimidazo[1,5-a]pyrazin-8(7H)-one derivatives as potent BRD4 inhibitors and evaluated their BRD4 inhibitory activities in vitro and anti-proliferation effects on tumor cells. Gratifyingly, compound 10j exhibited robust potency of BRD4(1) and BRD4(2) inhibition with IC50 values of 130 and 76 nM respectively. Docking studies were performed to explain the structure-activity relationship. Furthermore, compound 10j potently inhibited cell proliferation in BRD4-sensitive cell lines HL-60 and MV4-11 with IC50 value of 0.57 and 0.18 mu M respectively. Activity on BRD4-independent K562 cell was weaker than on BRD4-sensitive lines. Overall, these results suggest that compound 10j is a potential BRD4 inhibitor deserving further investigation for cancer treatment. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：2482 / 2490

页数：9

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