title: Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530.
abstract: AZD0530, an orally available Src inhibitor, demonstrated potent antimigratory and anti-invasive effects in vitro, and inhibited metastasis in a murine model of bladder cancer. Antiproliferative activity of AZD0530 in vitro varied between cell lines (IC(50) 0.2 ->10μM). AZD0530 inhibited tumor growth in 4/10 xenograft models tested and dynamically inhibited in vivo phosphorylation of Src substrates paxillin and FAK in both growth-inhibition-resistant and -sensitive xenografts. The activity of AZD0530 in NBT-II bladder cancer cells in vitro was consistent with inhibition of cell migration and stabilization of cell-cell adhesion. These data suggest a dominant anti-invasive pharmacology for AZD0530 that may limit tumor progression in a range of cancers. AZD0530 is currently in Phase II clinical trials.
authors.affiliation: Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield Cheshire, SK10 4TG, UK. timgreen350@googlemail.com
authors.forename: Tim P
authors.initials: TP
authors.lastname: Green
authors.forename: Mike
authors.initials: M
authors.lastname: Fennell
authors.forename: Robin
authors.initials: R
authors.lastname: Whittaker
authors.forename: Jon
authors.initials: J
authors.lastname: Curwen
authors.forename: Vivien
authors.initials: V
authors.lastname: Jacobs
authors.forename: Jack
authors.initials: J
authors.lastname: Allen
authors.forename: Armelle
authors.initials: A
authors.lastname: Logie
authors.forename: Judith
authors.initials: J
authors.lastname: Hargreaves
authors.forename: D Mark
authors.initials: DM
authors.lastname: Hickinson
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
authors.forename: Paul
authors.initials: P
authors.lastname: Elvin
authors.forename: Brigitte
authors.initials: B
authors.lastname: Boyer
authors.forename: Neil
authors.initials: N
authors.lastname: Carragher
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Plé
authors.forename: Alun
authors.initials: A
authors.lastname: Bermingham
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Holdgate
authors.forename: Walter H J
authors.initials: WH
authors.lastname: Ward
authors.forename: Laurent F
authors.initials: LF
authors.lastname: Hennequin
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
authors.forename: Gerard F
authors.initials: GF
authors.lastname: Costello
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017322:Clinical Trials, Phase II as Topic; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009368:Neoplasm Transplantation; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D011923:Rats, Nude; D014183:Transplantation, Heterologous; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; D009363:Neoplasm Proteins; C496061:PXN protein, human; D051419:Paxillin; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C515233:saracatinib; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases