Structural basis for the activity of the RSK-specific inhibitor, SL0101
Autor: | David J. Maloney, Sidney M. Hecht, Jeffrey A. Smith, Deborah A. Lannigan |
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Rok vydání: | 2007 |
Předmět: |
Models
Molecular Alkylation Rhamnose Clinical Biochemistry Pharmaceutical Science Hydroxylation Biochemistry Structure-Activity Relationship chemistry.chemical_compound Adenosine Triphosphate Cell Line Tumor Drug Discovery Humans Structure–activity relationship Benzopyrans Kaempferols Binding site Protein Kinase Inhibitors Molecular Biology Molecular Structure biology Chemistry Kinase Ribosomal Protein S6 Kinases Monosaccharides Organic Chemistry In vitro Enzyme inhibitor biology.protein Molecular Medicine Signal transduction Pharmacophore Hydrophobic and Hydrophilic Interactions |
Zdroj: | Bioorganic & Medicinal Chemistry. 15:5018-5034 |
ISSN: | 0968-0896 |
Popis: | Inappropriate activity of p90 ribosomal S6 kinase (RSK) has been implicated in various human cancers as well as other pathologies. We previously reported the isolation, characterization, and synthesis of the natural product kaempferol 3-O-(3'',4''-di-O-acetyl-alpha-l-rhamnopyranoside), termed SL0101 [Smith, J. A.; Poteet-Smith, C. E.; Xu, Y.; Errington, T. M.; Hecht, S. M.; Lannigan, D. A. Cancer Res., 2005, 65, 1027-1034: Xu, Y.-M; Smith, J. A.; Lannigan, D. A.; Hecht, S. M. Bioorg. Med. Chem., 2006, 14, 3974-3977: Maloney, D. J.; Hecht, S. M. Org. Lett., 2005, 7, 1097-1099]. SL0101 is a potent and specific inhibitor of RSK; therefore, we performed an analysis of the structural basis for the inhibitory activity of this lead compound. In in vitro kinase assays we found that acylation of the rhamnose moiety and the 4', 5, and 7-hydroxyl groups are responsible for maintaining a high affinity interaction of RSK with SL0101. It is likely that the hydroxyl groups facilitate RSK binding through their ability to form hydrogen bonds. To determine whether the SL0101 derivatives were specific for inhibition of RSK we analyzed their ability to preferentially inhibit the growth of the human breast cancer line, MCF-7, compared to the normal human breast line, MCF-10A. We have previously validated this differential growth assay as a convenient readout for analyzing the specificity of RSK inhibitors [Smith, J. A.; Maloney, D. J.; Clark, D. E.; Xu, Y.-M.; Hecht, S. M.; Lannigan, D. A. Bioorg. Med. Chem., 2006, 14, 6034-6042]. We found that acylation of the rhamnose moiety was essential for maintaining the selectivity for RSK inhibition in intact cells. Further, the efficacy of SL0101 in intact cells is limited by cellular uptake as well as possible hydrolysis of the acetyl groups on the rhamnose moiety by ubiquitous intracellular esterases. These studies should facilitate the development of a RSK inhibitor, based on the SL0101 pharmacophore, as an anti-cancer chemotherapeutic agent. |
Databáze: | OpenAIRE |
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