Novel potent and selective inhibitors of p90 ribosomal S6 kinase reveal the heterogeneity of RSK function in MAPK-driven cancers
I Aronchik, BA Appleton, SE Basham, K Crawford… - Molecular cancer …, 2014 - AACR
I Aronchik, BA Appleton, SE Basham, K Crawford, M Del Rosario, LV Doyle, WF Estacio…
Molecular cancer research, 2014•AACRThe 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 …
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 …
Abstract
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.
Implications: Two novel potent and selective RSK inhibitors will now allow a full assessment of the potential of RSK as a therapeutic target for oncology. Mol Cancer Res; 12(5); 803–12. ©2014 AACR.
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