Homology model of RSK2 N-terminal kinase domain, structure-based identification of novel RSK2 inhibitors, and preliminary common pharmacophore.

Nguyen TL, Gussio R, Smith JA, Lannigan DA, Hecht SM, Scudiero DA, Shoemaker RH, Zaharevitz DW
Bioorg Med Chem. 2006 14 (17): 6097-105

PMID: 16723234 · DOI:10.1016/j.bmc.2006.05.001

Ribosomal S6 kinase 2 (RSK2) is a serine/threonine kinase that plays a role in human cancer and Coffin-Lowry syndrome and is comprised of two nonidentical kinase domains, each domain with its own ATP-binding site. RSK2 can be inactivated by different types of small organic molecules. Potent RSK2 inhibitors include the two classic bisindole maleimide PKC inhibitors, Ro31-8220 and GF109203X, and the natural product SL0101 that was shown to bind specifically to the ATP pocket of the N-terminal domain (NTD). In this paper, we present an atomic model of the RSK2 NTD (residues 68-323), which was built to simultaneously bind the distinctive molecular scaffolds of SL0101, Ro31-8220, and GF109203X. The RSK2 NTD model was used to identify two novel RSK2 inhibitors from the National Cancer Institute open chemical repository and to develop a preliminary structure-based pharmacophore model.

MeSH Terms (12)

Benzopyrans Binding Sites Indoles Kaempferols Models, Molecular Monosaccharides Naphthalenes Protein Conformation Protein Structure, Tertiary Pyrimidines Ribosomal Protein S6 Kinases, 90-kDa Structure-Activity Relationship

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