TY - JOUR
T1 - Improving the affinity of SL0101 for RSK using structure-based design
AU - Mrozowski, Roman M.
AU - Vemula, Rajender
AU - Wu, Bulan
AU - Zhang, Qi
AU - Schroeder, Benjamin R.
AU - Hilinski, Michael K.
AU - Clark, David E.
AU - Hecht, Sidney
AU - O'Doherty, George A.
AU - Lannigan, Deborah A.
PY - 2013/2/14
Y1 - 2013/2/14
N2 - 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.
AB - 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.
KW - Kaempferol 3- O -(3″,4″-di- O -acetyl-α- l -rhamnopyranoside)
KW - RSK
KW - SL0101
KW - kinase inhibitor
KW - p90 ribosomal S6 kinase
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U2 - 10.1021/ml300298v
DO - 10.1021/ml300298v
M3 - Article
AN - SCOPUS:84873942644
SN - 1948-5875
VL - 4
SP - 175
EP - 179
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 2
ER -