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

Tam Luong Nguyen, Rick Gussio, Jeffrey A. Smith, Deborah A. Lannigan, Sidney M. Hecht, Dominic A. Scudiero, Robert H. Shoemaker, Daniel W. Zaharevitz

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6097-6105
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number17
DOIs
StatePublished - Sep 1 2006
Externally publishedYes

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Keywords

  • ATP-binding site
  • Homology model
  • Ligand docking
  • Pharmacophore
  • Ribosomal S6 kinase 2
  • Virtual screening

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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