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RSK2 Binding Models Delineate Key Features for Activity.

ABSTRACT: Due to its overexpression and activation in human cancer cells and tissues, an emerging molecular target in cancer therapeutics is p90 ribosomal s6 kinase 2 (RSK2). While a growing number of RSK2 inhibitors have been reported in the literature, only the crystal structure of RSK2 in complex with an AMP analogue provides a structural basis for understanding RSK2 inhibition. To remedy this, we used our fluorescence polarization assay to determine the RSK2 activity for a set of structurally diverse compounds, and followed this by modeling their binding modes in an all-atom, energy refined crystal structure of RSK2. These binding models reveal that Val131 and Leu147 are key interaction sites for potent RSK2 inhibition. This structure-based pharmacophore is an important tool for new lead discovery and refinement.

SUBMITTER: Gussio R

PROVIDER: S-EPMC3094916 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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RSK2 Binding Models Delineate Key Features for Activity.

Gussio Rick R Currens Michael J MJ Scudiero Dominic A DA Smith Jeffrey A JA Lannigan Deborah A DA Shoemaker Robert H RH Zaharevitz Dan W DW Nguyen Tam Luong TL

Journal of chemical and pharmaceutical research 20100101 5

Due to its overexpression and activation in human cancer cells and tissues, an emerging molecular target in cancer therapeutics is p90 ribosomal s6 kinase 2 (RSK2). While a growing number of RSK2 inhibitors have been reported in the literature, only the crystal structure of RSK2 in complex with an AMP analogue provides a structural basis for understanding RSK2 inhibition. To remedy this, we used our fluorescence polarization assay to determine the RSK2 activity for a set of structurally diverse ...[more]

PMID: 21593990

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