Novel Potent and Selective Inhibitors of p90 Ribosomal S6 Kinase Reveal the Heterogeneity of RSK Function in MAPK-Driven Cancers

被引：62

作者：

Aronchik, Ida ^{[1
]}

Appleton, Brent A. ^{[1
]}

Basham, Stephen E. ^{[1
]}

Crawford, Kenneth ^{[1
]}

Del Rosario, Mercedita ^{[1
]}

Doyle, Laura V. ^{[1
]}

Estacio, William F. ^{[1
]}

Lan, Jiong ^{[2
]}

Lindvall, Mika K. ^{[1
]}

Luu, Catherine A. ^{[1
]}

Ornelas, Elizabeth ^{[1
]}

Venetsanakos, Eleni ^{[1
]}

Shafer, Cynthia M. ^{[1
]}

Jefferson, Anne B. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, Emeryville, CA 94608 USA

[2] Shanghai Haiyan Pharmaceut Technol Co Ltd, Shanghai, Peoples R China

来源：

MOLECULAR CANCER RESEARCH | 2014年 / 12卷 / 05期

关键词：

BOX-BINDING PROTEIN-1; EPITHELIAL-CELLS; BREAST-CANCER; IN-VIVO; YB-1; PHOSPHORYLATION; GENE; TRANSCRIPTION; ACTIVATION; EXPRESSION;

D O I：

10.1158/1541-7786.MCR-13-0595

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The p90 ribosomal S6 kinase (RSK) family of serine/threonine kinases is expressed in a variety of cancers and its substrate phosphorylation has been implicated in direct regulation of cell survival, proliferation, and cell polarity. This study characterizes and presents the most selective and potent RSK inhibitors known to date, LJH685 and LJI308. Structural analysis confirms binding of LJH685 to the RSK2 N-terminal kinase ATP-binding site and reveals that the inhibitor adopts an unusual nonplanar conformation that explains its excellent selectivity for RSK family kinases. LJH685 and LJI308 efficiently inhibit RSK activity in vitro and in cells. Furthermore, cellular inhibition of RSK and its phosphorylation of YB1 on Ser102 correlate closely with inhibition of cell growth, but only in an anchorage-independent growth setting, and in a subset of examined cell lines. Thus, RSK inhibition reveals dynamic functional responses among the inhibitor-sensitive cell lines, underscoring the heterogeneous nature of RSK dependence in cancer. (C) 2014 AACR.

引用

收藏

页码：803 / 812

页数：10

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