文摘
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鈥?4鈥?di-O-acetyl-伪-l-rhamnopyranoside)) has been shown to be an RSK selective inhibitor. However, the Ki for SL0101 is 1 渭M 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鈥?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鈥?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鈥?n-propyl analogue for RSK will aid in the design of future compounds for in vivo use.
Keywords:
Kaempferol 3-O-(3鈥?4鈥?di-O-acetyl-伪-l-rhamnopyranoside); SL0101; RSK; p90 ribosomal S6 kinase; kinase inhibitor