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

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 a 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 two-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.

• Authors: Roman M Mrozowski, Rajender Vemula, Bulan Wu, Qi Zhang, Benjamin R Schroeder, Michael K Hilinski, David E Clark, Sidney M Hecht, George A O'Doherty, Deborah A Lannigan
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 4 Issue 2 Pg. 175-179 (Feb 14 2012) ISSN: 1948-5875 [Print] United States
• PMID: 23519677 (Publication Type: Journal Article)