title: Analogs of the RSK inhibitor SL0101: optimization of in vitro biological stability.
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.
authors.affiliation: Center for Cell Signaling, University of Virginia, Charlottesville, VA 22908, USA. mh6cu@virginia.edu
authors.forename: Michael K
authors.initials: MK
authors.lastname: Hilinski
authors.forename: Roman M
authors.initials: RM
authors.lastname: Mrozowski
authors.forename: David E
authors.initials: DE
authors.lastname: Clark
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Lannigan
mesh_terms: D000215:Acylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D009005:Monosaccharides / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D009005:Monosaccharides; D047428:Protein Kinase Inhibitors; C497449:SL0101; D038744:Ribosomal Protein S6 Kinases, 90-kDa