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

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

Authors :
Mrozowski RM
Vemula R
Wu B
Zhang Q
Schroeder BR
Hilinski MK
Clark DE
Hecht SM
O'Doherty GA
Lannigan DA
Source :
ACS medicinal chemistry letters [ACS Med Chem Lett] 2012 Feb 14; Vol. 4 (2), pp. 175-179. Date of Electronic Publication: 2012 Dec 26.
Publication Year :
2012

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.

Details

Language :
English
ISSN :
1948-5875
Volume :
4
Issue :
2
Database :
MEDLINE
Journal :
ACS medicinal chemistry letters
Publication Type :
Academic Journal
Accession number :
23519677
Full Text :
https://doi.org/10.1021/ml300298v