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	Tim P Green, Mike Fennell, Robin Whittaker, Jon Curwen, Vivien Jacobs, Jack Allen, Armelle Logie, Judith Hargreaves, D Mark Hickinson, Robert W Wilkinson, Paul Elvin, Brigitte Boyer, Neil Carragher, Patrick A Plé, Alun Bermingham, Geoffrey A Holdgate, Walter H J Ward, Laurent F Hennequin, Barry R Davies, Gerard F Costello
Journal	Molecular oncology (Mol Oncol) Vol. 3 Issue 3 Pg. 248-61 (Jun 2009) ISSN: 1878-0261 [Electronic] United States
PMID	19393585 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Benzodioxoles Neoplasm Proteins PXN protein, human Paxillin Protein Kinase Inhibitors Quinazolines saracatinib Focal Adhesion Kinase 1 PTK2 protein, human src-Family Kinases
Topics	Administration, Oral Animals Antineoplastic Agents (pharmacology) Benzodioxoles (pharmacology) Cell Line, Tumor Cell Movement (drug effects) Cell Proliferation (drug effects) Clinical Trials, Phase II as Topic Focal Adhesion Kinase 1 (metabolism) Humans Mice Mice, Nude NIH 3T3 Cells Neoplasm Invasiveness Neoplasm Proteins (antagonists & inhibitors, metabolism) Neoplasm Transplantation Paxillin (metabolism) Phosphorylation (drug effects) Protein Kinase Inhibitors (pharmacology) Quinazolines (pharmacology) Rats Rats, Nude Transplantation, Heterologous Urinary Bladder Neoplasms (drug therapy, enzymology, pathology) Xenograft Model Antitumor Assays src-Family Kinases (antagonists & inhibitors, metabolism)

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