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 Hecht, Dominic A. Scudiero, Robert H. Shoemaker, Daniel W. Zaharevitz

Research output: Contribution to journalArticle

38 Citations (Scopus)

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

Fingerprint

Phosphotransferases
Coffin-Lowry Syndrome
Adenosine Triphosphate
National Cancer Institute (U.S.)
Protein-Serine-Threonine Kinases
Biological Products
Scaffolds
ribosomal protein S6 kinase, 90kDa, polypeptide 3
Binding Sites
Molecules
Neoplasms
SL0101
Ro 31-8220
bisindolylmaleimide I

Keywords

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

ASJC Scopus subject areas

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

Cite this

Homology model of RSK2 N-terminal kinase domain, structure-based identification of novel RSK2 inhibitors, and preliminary common pharmacophore. / Nguyen, Tam Luong; Gussio, Rick; Smith, Jeffrey A.; Lannigan, Deborah A.; Hecht, Sidney; Scudiero, Dominic A.; Shoemaker, Robert H.; Zaharevitz, Daniel W.

In: Bioorganic and Medicinal Chemistry, Vol. 14, No. 17, 01.09.2006, p. 6097-6105.

Research output: Contribution to journalArticle

Nguyen, Tam Luong ; Gussio, Rick ; Smith, Jeffrey A. ; Lannigan, Deborah A. ; Hecht, Sidney ; Scudiero, Dominic A. ; Shoemaker, Robert H. ; Zaharevitz, Daniel W. / Homology model of RSK2 N-terminal kinase domain, structure-based identification of novel RSK2 inhibitors, and preliminary common pharmacophore. In: Bioorganic and Medicinal Chemistry. 2006 ; Vol. 14, No. 17. pp. 6097-6105.
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