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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Center for Cell Signaling, Departments of 2 Pathology and 3 Chemistry, and 4 Microbiology, University of Virginia, Charlottesville, Virginia
Requests for reprints: Jeffrey A. Smith, Center for Cell Signaling, University of Virginia Health Science Center, Box 800577, Hospital West, 7041 Multistory Building, Charlottesville, VA 22908-0577. Phone: 434-924-1152; Fax: 434-924-1236; E-mail: jas8j{at}virginia.edu.
p90 ribosomal S6 kinase (RSK) is an important downstream effector of mitogen-activated protein kinase, but its biological functions are not well understood. We have now identified the first small-molecule, RSK-specific inhibitor, which we isolated from the tropical plant Forsteronia refracta. We have named this novel inhibitor SL0101. SL0101 shows remarkable specificity for RSK. The major determinant of SL0101-binding specificity is the unique ATP-interacting sequence in the amino-terminal kinase domain of RSK. SL0101 inhibits proliferation of the human breast cancer cell line MCF-7, producing a cell cycle block in G1 phase with an efficacy paralleling its ability to inhibit RSK in intact cells. RNA interference of RSK expression confirmed that RSK regulates MCF-7 proliferation. Interestingly, SL0101 does not alter proliferation of a normal human breast cell line MCF-10A, although SL0101 inhibits RSK in these cells. We show that RSK is overexpressed in 
50% of human breast cancer tissue samples, suggesting that regulation of RSK has been compromised. Thus, we show that RSK has an unexpected role in proliferation of transformed cells and may be a useful new target for chemotherapeutic agents. SL0101 will provide a powerful new tool to dissect the molecular functions of RSK in cancer cells.
Key Words: ribosomal S6 kinase • signal transduction • small-molecule kinase inhibitor • cancer
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