BRD4 Structure-Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536

被引：74

作者：

Chen, Lijia ^{[1
]}

Yap, Jeremy L. ^{[1
]}

Yoshioka, Makoto ^{[2
]}

Lanning, Maryanna E. ^{[1
]}

Fountain, Rachel N. ^{[1
]}

Raje, Mithun ^{[1
]}

Scheenstra, Jacob A. ^{[1
]}

Strovel, Jeffrey W.

Fletcher, Steven ^{[1
,3
]}

机构：

[1] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA

[2] ConverGene, Gaithersburg, MD 20878 USA

[3] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 07期

关键词：

Bromodomain; BRD; BET; protein-protein interaction; kinase; BI-2536; SMALL-MOLECULE INHIBITORS; ACUTE MYELOID-LEUKEMIA; C-MYC; PROTEIN-PROTEIN; TARGET; CANCER; POLYPHARMACOLOGY; DIMERIZATION; 10074-G5;

D O I：

10.1021/acsmedchemlett.5b00084

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A focused library of analogues of the dual PLK1 kinase/BRD4 bromodomain inhibitor BI-2536 was prepared and then analyzed for BRD4 and PLK1 inhibitory activities. Particularly, replacement of the cyclopentyl group with a 3-bromobenzyl moiety afforded the most potent BRD4 inhibitor of the series (39j) with a K-i = 8.7 nM, which was equipotent against PLK1. The superior affinity of 39j over the parental compound to BRD4 possibly derives from improved interactions with the WPF shelf. Meanwhile, substitution of the pyrimidine NH with an oxygen atom reversed the PLK1/BRD4 selectivity to convert BI-2536 into a BRD4-selective inhibitor, likely owing to the loss of a critical hydrogen bond in PLK1. We believe further fine-tuning will furnish a BRD4 "magic bullet" or an even more potent PLK1/BRD4 dual inhibitor toward the expansion and improved efficacy of the chemotherapy arsenal.

引用

页码：764 / 769

页数：6

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