Improving the affinity of SL0101 for RSK using structure-based design

Roman M. Mrozowski, Rajender Vemula, Bulan Wu, Qi Zhang, Benjamin R. Schroeder, Michael K. Hilinski, David E. Clark, Sidney Hecht, George A. O'Doherty, Deborah A. Lannigan

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Enhanced activity of the Ser/Thr protein kinase, RSK, is associated with transformation and metastasis, which suggests that RSK is an attractive drug target. The natural product SL0101 (kaempferol 3-O-(3″,4″-di-O- acetyl-α-L-rhamnopyranoside)) has been shown to be an RSK selective inhibitor. However, the Ki for SL0101 is 1 μM with a half-life of less than 30 min in vivo. To identify analogues with improved efficacy we designed a set of analogues based on the crystallographic model of SL0101 in complex with the RSK2 N-terminal kinase domain. We identified an analogue with a 5″-n-propyl group on the rhamnose that has >40-fold improved affinity for RSK relative to SL0101 in an in vitro kinase assay. This analogue preferentially inhibited the proliferation of the human breast cancer line, MCF-7, versus the normal untransformed breast line, MCF-10A, which is consistent with results using SL0101. However, the efficacy of the 5″-n-propyl analogue to inhibit MCF-7 proliferation was only 2-fold better than for SL0101, which we hypothesize is due to limited membrane permeability. The improved affinity of the 5″-n-propyl analogue for RSK will aid in the design of future compounds for in vivo use.

Original languageEnglish (US)
Pages (from-to)175-179
Number of pages5
JournalACS Medicinal Chemistry Letters
Issue number2
StatePublished - Feb 14 2013


  • Kaempferol 3- O -(3″,4″-di- O -acetyl-α- l -rhamnopyranoside)
  • RSK
  • SL0101
  • kinase inhibitor
  • p90 ribosomal S6 kinase

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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