Discovery of Potent and Selective RSK Inhibitors as Biological Probes

被引：47

作者：

Jain, Rama ^{[1
]}

Mathur, Michelle ^{[1
]}

Lan, Jiong ^{[1
]}

Costales, Abran ^{[1
]}

Atallah, Gordana ^{[1
]}

Ramurthy, Savithri ^{[1
]}

Subramanian, Sharadha ^{[1
]}

Setti, Lina ^{[1
]}

Feucht, Paul ^{[1
]}

Warne, Bob ^{[1
]}

Doyle, Laura ^{[1
]}

Basham, Stephen ^{[1
]}

Jefferson, Anne B. ^{[1
]}

Lindvall, Mika ^{[1
]}

Appleton, Brent A. ^{[1
]}

Shafer, Cynthia M. ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Global Discovery Chem Oncol & Exploratory Chem, Emeryville, CA 94608 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 17期

关键词：

RIBOSOMAL S6 KINASE; PHOSPHORYLATION; BI-D1870; PATHWAY; DESIGN; FAMILY; CELLS;

D O I：

10.1021/acs.jmedchem.5b00450

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

While the p90 ribosomal S6 kinase (RSK) family has been implicated in multiple tumor cell functions, the full understanding of this kinase family has been restricted by the lack of highly selective inhibitors. A bis-phenol pyrazole was identified from high-throughput screening as an inhibitor of the N-terminal kinase of RSK2. Structure-based drug design using crystallography, conformational analysis, and scaffold morphing resulted in highly optimized difluorophenol pyridine inhibitors of the RSK kinase family as demonstrated cellularly by the inhibition of YB1 phosphorylation. These compounds provide for the first time in vitro tools with an improved selectivity and potency profile to examine the importance of RSK signaling in cancer cells and to fully evaluate RSK as a therapeutic target.

引用

页码：6766 / 6783

页数：18

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