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

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• 作者：Lijia Chen ; Jeremy L. Yap ; Makoto Yoshioka ; Maryanna E. Lanning ; Rachel N. Fountain ; Mithun Raje ; Jacob A. Scheenstra ; Jeffrey W. Strovel ; Steven Fletcher
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：July 9, 2015
• 年：2015
• 卷：6
• 期：7
• 页码：764-769
• 全文大小：328K
• ISSN：1948-5875

文摘

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 鈥渕agic bullet鈥?or an even more potent PLK1/BRD4 dual inhibitor toward the expansion and improved efficacy of the chemotherapy arsenal.