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 journalArticle

13 Citations (Scopus)

Abstract

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
Volume4
Issue number2
DOIs
StatePublished - Feb 14 2013

Fingerprint

Phosphotransferases
Rhamnose
Biological Products
Protein Kinases
Half-Life
SL0101
Permeability
Assays
Breast
Breast Neoplasms
Neoplasm Metastasis
Membranes
Pharmaceutical Preparations
In Vitro Techniques
kaempferol

Keywords

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

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

Mrozowski, R. M., Vemula, R., Wu, B., Zhang, Q., Schroeder, B. R., Hilinski, M. K., ... Lannigan, D. A. (2013). Improving the affinity of SL0101 for RSK using structure-based design. ACS Medicinal Chemistry Letters, 4(2), 175-179. https://doi.org/10.1021/ml300298v

Improving the affinity of SL0101 for RSK using structure-based design. / Mrozowski, Roman M.; Vemula, Rajender; Wu, Bulan; Zhang, Qi; Schroeder, Benjamin R.; Hilinski, Michael K.; Clark, David E.; Hecht, Sidney; O'Doherty, George A.; Lannigan, Deborah A.

In: ACS Medicinal Chemistry Letters, Vol. 4, No. 2, 14.02.2013, p. 175-179.

Research output: Contribution to journalArticle

Mrozowski, RM, Vemula, R, Wu, B, Zhang, Q, Schroeder, BR, Hilinski, MK, Clark, DE, Hecht, S, O'Doherty, GA & Lannigan, DA 2013, 'Improving the affinity of SL0101 for RSK using structure-based design', ACS Medicinal Chemistry Letters, vol. 4, no. 2, pp. 175-179. https://doi.org/10.1021/ml300298v
Mrozowski RM, Vemula R, Wu B, Zhang Q, Schroeder BR, Hilinski MK et al. Improving the affinity of SL0101 for RSK using structure-based design. ACS Medicinal Chemistry Letters. 2013 Feb 14;4(2):175-179. https://doi.org/10.1021/ml300298v
Mrozowski, Roman M. ; Vemula, Rajender ; Wu, Bulan ; Zhang, Qi ; Schroeder, Benjamin R. ; Hilinski, Michael K. ; Clark, David E. ; Hecht, Sidney ; O'Doherty, George A. ; Lannigan, Deborah A. / Improving the affinity of SL0101 for RSK using structure-based design. In: ACS Medicinal Chemistry Letters. 2013 ; Vol. 4, No. 2. pp. 175-179.
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