title: Biological characterization of ETP-46321 a selective and efficacious inhibitor of phosphoinositide-3-kinases.
abstract: Inhibitors of PI3K signaling are of great therapeutic interest in oncology. The phosphoinositide-3-kinase signaling pathway is activated in a variety of solid and non-solid tumors. We have identified an imidazopyrazine derivative, ETP-46321, as a potent inhibitor of PI3Kα [Formula: see text]. The compound was 6 times less potent towards PI3Kδ and more than 200 and 60 times less potent at inhibiting PI3Kβ and PI3Kγ and did not significantly inhibit the related phosphoinositide-3-kinase-related protein kinase family kinases mTOR or DNA PK (IC(50)'s > 5 μM), or an additional 287 protein kinases that were screened. ETP-46321 inhibited PI3K signaling in treated tumor cell lines, induced cell cycle arrest and inhibited VEGF-dependent sprouting of HUVEC cells. The compound was anti-proliferative and synergized with both cytotoxic and targeted therapeutics. The compound induced a reduction in the phosphorylation of Akt in U87 MG xenografts after a single treatment. The growth of colon and lung cancinoma HT-29 and A549 xenografts was delayed by once a day treatment with ETP-46321. The compound synergized with Doxotaxel in a model of ovarian cancer.
authors.affiliation: Health Research Institut Biocruces, Cruces Hospital, Plaza Cruces s/n, Baracaldo 48903, Spain.
authors.forename: Teresa G
authors.initials: TG
authors.lastname: Granda
authors.forename: David
authors.initials: D
authors.lastname: Cebrián
authors.forename: Sonia
authors.initials: S
authors.lastname: Martínez
authors.forename: Patricia Villanueva
authors.initials: PV
authors.lastname: Anguita
authors.forename: Estela Casas
authors.initials: EC
authors.lastname: López
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Link
authors.forename: Teresa
authors.initials: T
authors.lastname: Merino
authors.forename: Joaquín
authors.initials: J
authors.lastname: Pastor
authors.forename: Beatriz G
authors.initials: BG
authors.lastname: Serelde
authors.forename: Sandra
authors.initials: S
authors.lastname: Peregrina
authors.forename: Irene
authors.initials: I
authors.lastname: Palacios
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Albarran
authors.forename: Antonio
authors.initials: A
authors.lastname: Cebriá
authors.forename: Milagros
authors.initials: M
authors.lastname: Lorenzo
authors.forename: Patricia
authors.initials: P
authors.lastname: Alonso
authors.forename: Jesús
authors.initials: J
authors.lastname: Fominaya
authors.forename: Ana Rodríguez
authors.initials: AR
authors.lastname: López
authors.forename: James R
authors.initials: JR
authors.lastname: Bischoff
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011719:Pyrazines / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011719:Pyrazines; C574806:ETP-46321