title: Novel potent and selective inhibitors of p90 ribosomal S6 kinase reveal the heterogeneity of RSK function in MAPK-driven cancers.
abstract: The p90 ribosomal S6 kinase (RSK) family of serine/threonine kinases is expressed in a variety of cancers and its substrate phosphorylation has been implicated in direct regulation of cell survival, proliferation, and cell polarity. This study characterizes and presents the most selective and potent RSK inhibitors known to date, LJH685 and LJI308. Structural analysis confirms binding of LJH685 to the RSK2 N-terminal kinase ATP-binding site and reveals that the inhibitor adopts an unusual nonplanar conformation that explains its excellent selectivity for RSK family kinases. LJH685 and LJI308 efficiently inhibit RSK activity in vitro and in cells. Furthermore, cellular inhibition of RSK and its phosphorylation of YB1 on Ser102 correlate closely with inhibition of cell growth, but only in an anchorage-independent growth setting, and in a subset of examined cell lines. Thus, RSK inhibition reveals dynamic functional responses among the inhibitor-sensitive cell lines, underscoring the heterogeneous nature of RSK dependence in cancer.
  
  
  CONCLUSIONS
  Two novel potent and selective RSK inhibitors will now allow a full assessment of the potential of RSK as a therapeutic target for oncology.
authors.affiliation: Authors' Affiliations: Novartis Institutes for BioMedical Research, Emeryville, California; and 2Shanghai Haiyan Pharmaceutical Technology Co., Ltd., Shanghai.
authors.forename: Ida
authors.initials: I
authors.lastname: Aronchik
authors.forename: Brent A
authors.initials: BA
authors.lastname: Appleton
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Basham
authors.forename: Kenneth
authors.initials: K
authors.lastname: Crawford
authors.forename: Mercedita
authors.initials: M
authors.lastname: Del Rosario
authors.forename: Laura V
authors.initials: LV
authors.lastname: Doyle
authors.forename: William F
authors.initials: WF
authors.lastname: Estacio
authors.forename: Jiong
authors.initials: J
authors.lastname: Lan
authors.forename: Mika K
authors.initials: MK
authors.lastname: Lindvall
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Luu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ornelas
authors.forename: Eleni
authors.initials: E
authors.lastname: Venetsanakos
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Shafer
authors.forename: Anne B
authors.initials: AB
authors.lastname: Jefferson
mesh_terms: D000595:Amino Acid Sequence; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D020928:Mitogen-Activated Protein Kinases