title: Homology model of RSK2 N-terminal kinase domain, structure-based identification of novel RSK2 inhibitors, and preliminary common pharmacophore.
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.
authors.affiliation: Target Structure-based Drug Discovery Group, SAIC-Frederick, Inc., NCI Frederick, Frederick, MD 21702, USA. nguyent@mail.ncifcrf.gov
authors.forename: Tam Luong
authors.initials: TL
authors.lastname: Nguyen
authors.forename: Rick
authors.initials: R
authors.lastname: Gussio
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Smith
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Lannigan
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Hecht
authors.forename: Dominic A
authors.initials: DA
authors.lastname: Scudiero
authors.forename: Robert H
authors.initials: RH
authors.lastname: Shoemaker
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Zaharevitz
mesh_terms: D001578:Benzopyrans / Q000737:chemistry; D001665:Binding Sites; D007211:Indoles / Q000737:chemistry; D044949:Kaempferols / Q000737:chemistry; D008958:Models, Molecular; D009005:Monosaccharides / Q000737:chemistry; D009281:Naphthalenes / Q000737:chemistry; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001578:Benzopyrans; C514278:GFX 109203x; D007211:Indoles; D044949:Kaempferols; D009005:Monosaccharides; C514279:NSC 356821; C514280:NSC 51023; D009281:Naphthalenes; D011743:Pyrimidines; C497449:SL0101; C006552:kaempferol; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; C064758:Ro 31-8220