title: 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 minin 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 anin vitrokinase 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 forin vivouse.
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University, Nashville, TN.
authors.forename: Roman M
authors.initials: RM
authors.lastname: Mrozowski
authors.forename: Rajender
authors.initials: R
authors.lastname: Vemula
authors.forename: Bulan
authors.initials: B
authors.lastname: Wu
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Schroeder
authors.forename: Michael K
authors.initials: MK
authors.lastname: Hilinski
authors.forename: David E
authors.initials: DE
authors.lastname: Clark
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Hecht
authors.forename: George A
authors.initials: GA
authors.lastname: O'Doherty
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Lannigan
keywords: 4″-di-O-acetyl-a-L-rhamnopyranoside); Kaempferol 3-O-(3″; RSK; SL0101; kinase inhibitor; p90 ribosomal S6 kinase