title: Development of organometallic S6K1 inhibitors.
abstract: Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically inhibit S6K1 using a strategy previously used to target other kinases. Biochemical data demonstrate that EM5 and FL772 inhibit the kinase with IC50 value in the low nanomolar range at 100 μM ATP and that the more potent FL772 compound has a greater than 100-fold specificity over S6K2. The crystal structures of S6K1 bound to staurosporine, EM5, and FL772 reveal that the EM5 and FL772 inhibitors bind in the ATP binding pocket and make S6K1-specific contacts, resulting in changes to the p-loop, αC helix, and αD helix when compared to the staurosporine-bound structure. Cellular data reveal that FL772 is able to inhibit S6K phosphorylation in yeast cells. Together, these studies demonstrate that potent, selective, and cell permeable S6K1 inhibitors can be prepared and provide a scaffold for future development of S6K inhibitors with possible therapeutic applications.
authors.affiliation: The Wistar Institute , 3601 Spruce Street, Philadelphia, Pennsylvania 19104, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Qin
authors.forename: Rajathees
authors.initials: R
authors.lastname: Rajaratnam
authors.forename: Li
authors.initials: L
authors.lastname: Feng
authors.forename: Jemilat
authors.initials: J
authors.lastname: Salami
authors.forename: Julie S
authors.initials: JS
authors.lastname: Barber-Rotenberg
authors.forename: John
authors.initials: J
authors.lastname: Domsic
authors.forename: Patricia
authors.initials: P
authors.lastname: Reyes-Uribe
authors.forename: Haiying
authors.initials: H
authors.lastname: Liu
authors.forename: Weiwei
authors.initials: W
authors.lastname: Dang
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
authors.forename: Jessie
authors.initials: J
authors.lastname: Villanueva
authors.forename: Eric
authors.initials: E
authors.lastname: Meggers
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D015153:Blotting, Western; D045744:Cell Line, Tumor; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry
chemical_list: D009942:Organometallic Compounds; D047428:Protein Kinase Inhibitors; D012428:Ruthenium; D000255:Adenosine Triphosphate; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1