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

  1. Author:
    Nguyen, T. L.
    Gussio, R.
    Smith, J. A.
    Lannigan, D. A.
    Hecht, S. M.
    Scudiero, D. A.
    Shoemaker, R. H.
    Zaharevitz, D. W.

  2. Author Address

    SAIC Frederick Inc, NCI Frederick, Target Structure Based Drug Discovery Grp, Frederick, MD 21702 USA. NCI, Dev Therapeut Program, Informat Technol Branch, Target Struct Based Drug Discovery Grp, Frederick, MD 21702 USA. Univ Virginia, Dept Pathol, Ctr Cell Signaling, Charlottesville, VA 22908 USA. Univ Virginia, Dept Microbiol, Ctr Cell Signaling, Charlottesville, VA 22908 USA. SAIC Frederick Inc, NCI Frederick, Screening Technol Branch, Charlottesville, VA 22901 USA. NCI, Dev Therapeut Program, Screening Technol Branch, Frederick, MD 21702 USA.;Nguyen, TL, SAIC Frederick Inc, NCI Frederick, Target Structure Based Drug Discovery Grp, Frederick, MD 21702 USA.;nguyent@mail.ncifcrf.gov
    1. Year: 2006
    2. Date: Sep
  2. Journal: Bioorganic & Medicinal Chemistry
    1. 14
    2. 17
    3. Pages: 6097-6105
  4. Type of Article: Article
  5. ISSN: 0968-0896
  1. 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. Published by Elsevier Ltd.

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  2. DOI: 10.1016/j.bmc.2006.05.001
  3. View record in Web of Science®
  4. WOS: 000239947500032

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