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Bioorg Med Chem Lett. 2012 May 1;22(9):3244-7. doi: 10.1016/j.bmcl.2012.03.033. Epub 2012 Mar 13.

Analogs of the RSK inhibitor SL0101: optimization of in vitro biological stability.

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  • 1Center for Cell Signaling, University of Virginia, Charlottesville, VA 22908, USA. mh6cu@virginia.edu

Abstract

The Ser/Thr protein kinase, RSK, is important in the etiology of tumor progression including invasion and motility. The natural product kaempferol-3-O-(3″,4″-di-O-acetyl-α-l-rhamnopyranoside), called SL0101, is a highly specific RSK inhibitor. Acylation of the rhamnose moiety is necessary for high affinity binding and selectivity. However, the acetyl groups can be cleaved by esterases, which accounts for the poor in vitro biological stability of SL0101. To address this problem a series of analogs containing acetyl group replacements were synthesized and their in vitro stability evaluated. Monosubstituted carbamate analogs of SL0101 showed improved in vitro biological stability while maintaining specificity for RSK. These results should facilitate the development of RSK inhibitors derived from SL0101 as anticancer agents.

Copyright © 2012 Elsevier Ltd. All rights reserved.

PMID:
22464132
[PubMed - indexed for MEDLINE]
PMCID:
PMC3331937
Free PMC Article

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