TY - JOUR
T1 - Homology model of RSK2 N-terminal kinase domain, structure-based identification of novel RSK2 inhibitors, and preliminary common pharmacophore
AU - Nguyen, Tam Luong
AU - Gussio, Rick
AU - Smith, Jeffrey A.
AU - Lannigan, Deborah A.
AU - Hecht, Sidney M.
AU - Scudiero, Dominic A.
AU - Shoemaker, Robert H.
AU - Zaharevitz, Daniel W.
N1 - Funding Information:
This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract NO1-CO-12400 and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government.
PY - 2006/9/1
Y1 - 2006/9/1
N2 - 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.
AB - 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.
KW - ATP-binding site
KW - Homology model
KW - Ligand docking
KW - Pharmacophore
KW - Ribosomal S6 kinase 2
KW - Virtual screening
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U2 - 10.1016/j.bmc.2006.05.001
DO - 10.1016/j.bmc.2006.05.001
M3 - Article
C2 - 16723234
AN - SCOPUS:33746049159
VL - 14
SP - 6097
EP - 6105
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 17
ER -